Biological and Health Sciences

Mohamed Abdel Hakeem, PhD

ASSISTANT PROFESSOR, SCHOOL OF MEDICINE, PATHOLOGY

Modulating preexisting chronic inflammation to enhance vaccine-induced memory

Vaccine protective capacity relies on memory B and T lymphocytes (Bmem/Tmem). Individuals living with chronic diseases, e.g. chronic infection, exhibit inferior vaccine responses. Animal studies confirmed inferior recall responses by CD8 Tmem with preexisting chronic infection and cancer (hereafter inflm-Tmem). However, molecular imprints of persistent inflammation on Bmem/Tmem, and interventions to restore efficient recall responses are understudied. Previous studies and our data demonstrated arrested development, and skewed transcriptional and epigenetic landscapes of CD8 inflm-TMEM, with enriched proinflammatory signatures, e.g. type I interferon and interleukin 6, which signal downstream janus kinase 1/2 (JAK1/2). We hypothesize that preexisting infection would also skew molecular programs of Bmem and CD4-Tmem, and that JAK1/2 inhibitors (JAKi) would recover Bmem/Tmem normal differentiation in these hosts. For this, we will examine differentiation and recall responses of antigen-specific B and T cells responding to influenza in mice with preexisting chronic LCMV-Clone 13 with or without JAKi treatment, using high-dimensional (HD) flowcytometry and combined single-cell RNAseq/ATACseq (MultiOme) profiling. Our expertise in all proposed tools puts us in a unique position to address our objective: using FDA-approved therapeutics to recover efficient vaccine-induced memory and unraveling molecular mechanisms underlying skewed Bmem/Tmem differentiation in hosts with preexisting chronic disease. We push the envelope of innovation by combining HD-flowcytometry, functional assays, rechallenge models, and MultiOme profiling, to decipher mechanisms of compromised recall capacity that are understudied. We will gain unprecedented insights into lymphocyte biology and validate repurposing FDA-approved medications to enhance vaccine-induced memory in hosts with chronic disease.

Fikri Birey, PhD

ASSISTANT PROFESSOR, SCHOOL OF MEDICINE, HUMAN GENETICS

Functional Mapping of Neuropsychiatric Disease Variants at Scale in Human Neurons

Genetic testing has revolutionized the diagnosis of brain disorders, yet a critical bottleneck remains: the majority of identified genetic variants are classified as "variants of uncertain significance" (VUS), meaning their impact on health is unknown. This diagnostic ambiguity leaves patients and families without clear answers and limits the development of targeted treatments. The challenge is particularly acute for neuropsychiatric disorders, where understanding how genetic variants affect brain cell function requires studying human neurons, which is a a technically demanding endeavor that has resisted high-throughput approaches. This project addresses this challenge by developing a first-of-its-kind platform to systematically test the functional effects of thousands of disease-associated genetic variants in human neurons. We focus on CACNA1C, a gene encoding a calcium channel critical for brain function. Variants in CACNA1C are linked to multiple neuropsychiatric conditions including Timothy syndrome, schizophrenia, and major depression, yet over 2,000 CACNA1C variants remain functionally uncharacterized. Our approach combines two innovative technologies: multiplexed prime editing, which allows precise installation of many genetic variants simultaneously, and a biochemical tool that records calcium signaling activity in neurons. By measuring how each variant affects calcium channel function, we can classify variants as causing increased activity, decreased activity, or no change. We anticipate generating functional data for approximately 1,500 CACNA1C variants, transforming many VUS into clinically actionable classifications. This work establishes a generalizable framework that can be extended to other genes implicated in neuropsychiatric disorders, aimed at accelerating genetic diagnosis and personalized treatment strategies.

Deborah Bruner, PhD

PROFESSOR, NELL HODGSON WOODRUFF SCHOOL OF NURSING, ACADEMIC ADVANCEMENT

Microbial metabolite environments and HPV-permissive phenotypes in cervical cancer cells

Despite improvements in screening and treatment for cervical cancer (CxCa), over 1/3rd of affected women die of the disease. A critical barrier to improved outcomes is persistent Human Papillomavirus (HPV) infection, the etiologic agent of nearly all CxCa. Up to 55% of women exhibit persistent HPV following curative radiation therapy, and approximately 35% experience recurrence within two years. The vaginal microbiome (VM) has emerged as a key regulator of mucosal immunity, epithelial homeostasis, and susceptibility to viral infections. Healthy VMs are typically dominated by Lactobacillus crispatus, which maintains a lactic acid–rich environment that supports antiviral immunity and epithelial integrity. Dysbiotic states characterized by reduced Lactobacillus abundance and enrichment of anaerobes—particularly Prevotella spp. (as demonstrated in our published work) —are associated with elevated pro-inflammatory cytokines, reduced type I interferon activity, increased epithelial permeability, and greater susceptibility to infection. In CxCa, early studies suggest that VM influences HPV persistence and treatment response, yet the mechanistic basis is poorly understood. This will be the first study in the literature to define how microbial metabolite environments derived from dysbiotic (Prevotella-rich) or protective (L. crispatus–rich) communities regulate inflammatory signaling, antiviral responses, and HPV activity in CxCa cells, and to identify the specific bacterial metabolites responsible. This path of inquiry could lead from 2D to 3D models for assessing vaginal microbial communities and metabolites, and to targeted probiotic or post-probiotic (metabolite-based) therapies to minimize opportunistic taxa and maximize beneficial taxa to support overall healthier vaginal environments that are hostile to HPV persistence.

Cristina Ceriani, PhD

RESEARCH ASSOCIATE, NATIONAL PRIMATE RESEARCH CENTER, MICROBIOLOGY AND IMMUNOLOGY

Targeting HIV Reservoir Formation via PROTAC-Mediated Degradation of BCL-2 Family Proteins

Despite effective antiretroviral therapy (ART), HIV persists in a small population of long-lived, latently infected CD4⁺ T cells, known as the HIV reservoir. These cells can reactivate and reignite infection if therapy is interrupted, representing the main barrier to a cure. Current strategies, such as shock-and-kill approaches, largely target the reservoir after it is established and face challenges of incomplete elimination of infected cells, highlighting the need for complementary approaches that intervene earlier. One reason reservoir cells survive is their high expression of pro-survival proteins, particularly BCL-2 and BCL-xL. This project will test BCL-2/BCL-xL PROTACs, a novel class of molecules that selectively degrade specific target proteins rather than simply inhibiting them. By promoting degradation of BCL-2 and BCL-xL, PROTACs may render reservoir-forming cells more susceptible to natural cell death, potentially limiting the establishment of long-lived infected cells. We will use an in vitro HIV infection model with primary CD4⁺ T cells from healthy donors. The study will examine how PROTACs affect the survival of infected versus uninfected cells during early infection. We will measure whether PROTACs efficiently degrade BCL-2/BCL-xL, induce apoptosis, and reduce the number of infected cells, while mostly sparing uninfected CD4⁺ T cells. This pilot study provides an opportunity to generate proof-of-concept data on PROTAC-mediated disruption of HIV reservoir formation. These results may help identify lead candidates for further preclinical evaluation and inform future strategies that target survival pathways to limit the HIV reservoir.

Anthony Donsante, PhD

ASSISTANT PROFESSOR, SCHOOL OF MEDICINE, NEUROSURGERY

Targeting IGF binding proteins for the treatment of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) represents the most common adult motor neuron disease.  Only three drugs have been approved to treat this disorder, but their efficacy is modest.  Two factors have impeded the development of treatments for ALS.  First, the disorder is not monogenic, so there is no single gene or function to target.  Second, the events leading to MN dysfunction are complex and not well understood.  Toxicity of mutant proteins, oxidative damage, mitochondrial dysfunction, defects in axonal transport, and glutamate excitotoxicity likely all play a role in disease initiation and progression.    It has long been known that there are trophic factors that promote motor neuron survival and neurite outgrowth.  A number of protective factors have been investigated, including human insulin-like growth factor-1 (IGF-1).  IGF-1 is particularly interesting because it plays a role in axon maintenance.  In ALS, several proteins that inhibit IGF-1 signaling are increased, reducing its activity.  These proteins may also contribute to disease progression in other ways, as well.    This proposal will investigate the possibility that reducing the expression of these IGF-1 binding proteins will slow disease progression.  It will first show that the rat model faithful replicates this aspect of ALS.  It will then evaluate the role one IGF binding protein (IGFBP-5) has in promoting this disease using a genetic mouse model.  If successful, this research will open up many new avenues for treating diseases like ALS.

Adam Ericsen, PhD

ASSISTANT PROFESSOR, NATIONAL PRIMATE RESEARCH CENTER, MICROBIOLOGY AND IMMUNOLOGY

Genetic Basis of Generalized Epilepsy in Rhesus Macaques

Epilepsy is a common neurological disorder that affects over 50 million people worldwide and a third of epilepsy patients do not achieve seizure control, underscoring the need to develop better treatments. Rodent models are valuable for advancing our understanding of basic mechanism and underlying genetic epilepsy, however, key differences with humans limit their translational relevance. Non-human primates (NHP) offer a critical bridge between rodent models and human patients. Rhesus macaques (RMs) have sufficiently large brains to support clinically scalable devices and exhibit immune responses that closely mirror those of humans, which is critical for evaluating the safety of emerging gene therapies. Acute seizures models have been successfully used in NHP for the study of seizure mechanism and propagation, but as they are not epilepsy model per see, they are not ideal to test new therapy, study neuroplasticity or the chronobiology of seizure. A genetic RM epilepsy model would uniquely fulfill the need for a translational model that faithfully recapitulates the complex interactions between genetic, brain networks, physiology, and immune function observed in humans. Our interdisciplinary team of geneticist, epilepsy and behavioral neuroscientists identified a cohort of RMs in our colony with generalized seizures and related pedigree, suggesting that there is a heritable genetic contribution to the observed seizure phenotype within our RM colony. In this proposed URC pilot, we will explore the genetic contribution to generalized seizures in our RM cohort (Aim 1) and characterize the susceptibility of offspring to inherit the spontaneous seizure genotype from their mother (Aim 2).

Kiesha Fraser Doh, MD

ASSOCIATE PROFESSOR, SCHOOL OF MEDICINE, PEDIATRICS

Co-design of an Intervention (Hospital-based Violence Intervention Program-HVIP) to Provide Services to Violently Injured Youth

Firearm violence is the leading cause of death for American children, and Children’s Healthcare of Atlanta (CHOA) treats over 100 youth annually for gun injuries, mostly from interpersonal violence. These injuries disproportionately affect Black youth from historically marginalized neighborhoods and lead to lasting physical, emotional, and social challenges compounded by systemic inequities. To address this, we propose developing—a hospital-based violence intervention program (HVIP) created through a collaborative, community-driven process. The first phase focuses on defining the problem by engaging key stakeholders—youth with lived experience, caregivers, clinicians, community-based organizations, survivor advocates, violence interrupters, and hospital leadership—through focus groups and interviews. These conversations will identify shared and divergent needs, values, barriers, and priorities for HVIP development, as well as recommendations to improve system readiness. Next, stakeholders will participate in structured co-design sessions to translate these insights into actionable program components and workflows. This iterative process ensures the HVIP reflects community priorities, addresses real-world barriers, and builds trust. By centering on the voices of those most impacted, the program will be culturally responsive, feasible, and sustainable. This approach moves beyond traditional top-down program design. Instead, it creates a stakeholder-owned model that integrates trauma-informed care and equity principles from the start. This model aims to lay the foundation for a hospital-based violence intervention program that promotes healing, prevents reinjury, and strengthens resilience for youth and families affected by violence.

Danielle Giovenco, PhD

ASSISTANT PROFESSOR, ROLLINS SCHOOL OF PUBLIC HEALTH, GLOBAL HEALTH

Developing a Technology-Enabled Screening and Referral Tool to Support Mental Health, Safety, and Social Needs in Clinical Care

Healthcare systems increasingly recognize that patients’ health outcomes are shaped by co-occurring social and psychological needs. Yet frontline clinicians are often expected to identify and respond to these intersecting needs within brief clinical encounters using fragmented tools and workflows. As a result, screening and referral processes are frequently siloed and inconsistently implemented, limiting follow-through and contributing to inequities in care engagement. There is a critical need for clinician-centered approaches that support integrated identification, intervention, and referral for patients with complex needs. This project aims to adapt the evidence-based Screening, Brief Intervention, and Referral to Treatment (SBIRT) framework to support integrated screening for mental health, safety and violence exposure, and social determinants of health within routine clinical workflows. The objective is to generate a technology-enabled, beta-tested prototype of an adapted SBIRT tool that is acceptable, usable, and feasibly positioned for future pilot testing. Using a two-phase, mixed-methods implementation science approach, Phase 1 will engage clinicians and nurses in structured consensus-building using the qualitative Nominal Group Technique method to identify priority screening domains, workflow constraints, and technology features. Phase 2 will translate these priorities into a functional digital prototype developed in collaboration with Emory’s Department of Biomedical Informatics, followed by beta testing through structured usability sessions to iteratively refine protype design and decision-support features. This project will generate foundational evidence to support external funding applications (e.g., NIH R21/R34 and subsequent R01) and ultimately advance scalable, equity-oriented approaches to integrated screening and referral in real-world clinical care.

Jesse Handler, MD, PhD

ASSISTANT PROFESSOR, SCHOOL OF MEDICINE, HEMATOLOGY AND MEDICAL ONCOLOGY

Adipocyte–immune–tumor crosstalk driving clonal evolution and immune evasion in CRC peritoneal carcinomatosis

Peritoneal carcinomatosis from colorectal cancer (CRC-PC) is a devastating form of metastatic disease with limited therapeutic options and poor survival. Unlike liver or lung metastases, peritoneal tumors must establish a supportive niche de novo within the abdominal cavity, suggesting unique biological vulnerabilities. Our preliminary data demonstrate that peritoneal metastases harbor markedly greater cancer clonal diversity than liver metastases. Because the immune system normally restrains clonal diversity through selective elimination of immunogenic subclones (“immunologic pruning”), these findings point to impaired immune surveillance within the peritoneal niche.  Peritoneal metastases are embedded within adipose-rich environments, yet the role of adipocytes in CRC-PC progression remains poorly understood. Prior studies show that adipocytes can transfer lipids to cancer cells, promoting growth, while lipid uptake by immune cells suppresses anti-tumor function by impairing CD8⁺ T cell and NK cell cytotoxicity and enhancing regulatory T cell activity. Together, these observations support a model in which adipocyte-derived lipids simultaneously fuel tumor growth and blunt immune-mediated tumor control, enabling the persistence of diverse cancer subclones.  The objective of this project is to define how adipocytes and immune cells regulate cancer clonal diversity in the peritoneal niche and to identify metabolic vulnerabilities that enhance immunologic pruning. We hypothesize that peritoneal adipocytes suppress anti-tumor immunity and metabolically support low-fitness cancer subclones through lipid transfer. We will test this hypothesis by integrating spatial lipidomics and spatial transcriptomics in human CRC-PC tissues and by using barcoded mouse models to assess how obesity and metabolic modulation reshape clonal diversity.

Jessica Harding, PhD

ASSOCIATE PROFESSOR, SCHOOL OF MEDICINE, SURGERY

Identifying Care Gaps for Adults with Chronic Kidney Disease in the United States

This project aims to understand and address critical care gaps for Americans living with chronic kidney disease (CKD), a highly prevalent condition that imposes major health and economic burdens nationwide. It will evaluate how well existing guidelines on CKD screening, diagnosis, treatment, and monitoring are implemented in routine practice, recognizing that many patients do not receive care that could slow progression or prevent complications such as kidney failure and cardiovascular disease. The study will use Epic Cosmos, a large, integrated electronic health record database covering over 300 million patients across the United States, to capture CKD care across diverse health systems and settings. Using this resource, the project will follow patients along the full CKD care spectrum: from those at risk but undiagnosed, through initial diagnosis and treatment, to long-term monitoring for established CKD. It will assess whether high-risk individuals are appropriately screened, whether possible CKD is promptly and accurately identified, and whether patients receive recommended medications, referrals, and follow-up care. At each step, the study will examine differences by age, sex, race, socioeconomic status, insurance type, geography, and clinical setting to identify where gaps are greatest and which populations are most affected. The resulting national portrait of real-world CKD care, overcoming limitations of smaller or less complete datasets, will provide essential evidence to guide targeted interventions and policy changes aimed at ensuring more timely, equitable, and evidence-based care for people with CKD across the United States.

David Katz, PhD

ASSOCIATE PROFESSOR, SCHOOL OF MEDICINE, CELL BIOLOGY

The function of the histone acetylation inhibitor SET in mice and its contribution to human SET patient phenotypes

Development requires extensive epigenetic reprogramming to ensure that permissive chromatin states do not inappropriately persist across developmental or generational transitions. While DNA methylation and histone methylation are well-established targets of epigenetic reprogramming, histone acetylation is widely regarded as a transient modification that reflects ongoing transcriptional activity rather than epigenetic memory. Our recent work in C. elegans challenges this view. We demonstrated that loss of SPR-2, an inhibitor of histone acetyltransferases (INHAT), leads to progressive accumulation of histone acetylation across generations, accompanied by developmental delay, behavioral abnormalities, and germline mortality. These findings suggest that in worms histone acetylation can function as an epigenetic memory when mechanisms that normally restrain acetylation are disrupted. In mammals, SET (TAF-Iβ) is a conserved INHAT component that represses acetylation-dependent transcriptional programs and is essential for normal embryonic development. Complete loss of SET in mice causes early embryonic lethality with prominent developmental defects. Heterozygous SET mutations in humans are associated with neurodevelopmental delay, intellectual disability, behavioral abnormalities and craniofacial defects. Despite this, whether SET regulates histone acetylation during development and whether the misregulation of histone acetylation can contribute to defects later in development remains unknown. This project aims to determine whether loss of SET leads to abnormal histone acetylation and transcriptional disruption during mammalian development and whether these potential defects can contribute to phenotypes observed in human SET patients. This work will provide preliminary data on acetylation-based chromatin regulation for a subsequent NIH R01.

Mohd Khan, PhD

ASSISTANT PROFESSOR, SCHOOL OF MEDICINE, ORTHOPAEDICS

Joint Acidosis Regulates Synovial Inflammation via the Acid-Sensing Receptor GPR68 in Osteoarthritis

Osteoarthritis (OA) is the most common joint disease and a major cause of pain and disability. Although OA is often considered “wear-and-tear,” many patients develop inflammation of the synovial lining, which contributes to ongoing pain, swelling, and tissue damage. A central driver of this inflammation is the macrophage, an immune cell that accumulates in the synovium during OA. However, we still do not understand what early signals attract macrophages to the joint or what causes them to become inflammatory. One overlooked feature of the OA joint is acidosis, a drop in local pH that creates a more acidic environment. Recent evidence suggests that this acidity may influence macrophage behavior, but this idea has never been tested directly in joint tissues or in human macrophages. This project will take a two-step approach to answer this question. First, we will use a special imaging biosensor and spatial transcriptomics to determine when the joint becomes acidic during OA and whether these acidic periods correspond with increased macrophage presence or inflammatory “hotspots” in the synovium. Second, we will study human macrophages taken from OA synovium to test whether acidic conditions directly activate these cells or make them more likely to migrate toward inflamed areas, and whether an acid-sensing gene called GPR68 helps control this response. The results from this pilot study will establish a new research direction focused on how joint acidity shapes immune behavior in OA and will provide the foundation for future treatments aimed at reducing synovial inflammation and improving patient outcomes.

Rachel Kinsella, PhD

ASSISTANT PROFESSOR, SCHOOL OF MEDICINE, INFECTIOUS DISEASES

Immunothrombotic Mechanisms of Vascular Damage and Cardiovascular Disease Risk in Tuberculosis

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a leading global health threat, with long-term survivors facing an increased risk of cardiovascular disease (CVD), likely due to chronic inflammation and immune dysregulation. Recent evidence implicates neutrophils and the formation of neutrophil extracellular traps (NETs) as critical drivers of both TB pathology, atherogenesis and atherothrombosis. NETs not only fail to kill Mtb but exacerbate inflammation and tissue damage, potentially linking TB to accelerated vascular disease. Using a pro-atherosclerotic Apoe⁻/⁻ mouse model, this study aims to investigate how Mtb infection and TB induced NETs contribute to atherosclerotic plaque formation, vascular inflammation, and thromboinflammation. Specifically, the work will assess the effects of Mtb-induced NETs and platelet activation on plaque burden, endothelial damage, and immune remodeling across vascular and pulmonary compartments. Pharmacological inhibition of NETosis and depletion of platelets will test the therapeutic potential of targeting these pathways to mitigate CVD risk in TB. These studies will provide critical mechanistic insight into the intersection of infectious and cardiovascular disease and identify new strategies to improve long-term outcomes for TB survivors.

Dorothy Koveal, PhD

ASSISTANT PROFESSOR, SCHOOL OF MEDICINE, BIOMEDICAL ENGINEERING

Accelerating Fluorescent Biosensor Development to Create New Tools for Investigating the Neural Control of Movement

The basal ganglia, a phylogenetically-conserved set of deep brain nuclei, play a pivotal role in the control of movement. In the striatum, which is the primary input into the basal ganglia, loss of striatal dopamine results in debilitating motor deficits and is one of the primary phenotypes of Parkinson’s disease (PD). Despite its profound impact on movement in PD, we have yet to establish a mechanistic link between dopamine release and movement in the lab. A key missing element in current studies is simultaneous measurement of dopamine and the activity state of the downstream neurons that bind dopamine. However, we currently lack the genetically encoded biosensors required to carry out this measurement. We will address this challenge in three cross-cutting Aims that leverage the PI’s and Co-I’s respective expertise in two disciplines: (i) the development of a photostable red fluorescent calcium biosensor, which reports on neuronal activity (PI Dr. Koveal) and (ii) in vivo neural imaging in awake behaving animals (Co-I Dr. Markowitz). First and second, we will improve the in vivo performance of our lead biosensor candidate by increasing biosensor response size. To accelerate this aim, we have piloted a new biosensor screening system that will increase throughput by two orders of magnitude. Third, we will use the improved red calcium biosensor to resolve how dopamine modulates the excitability of downstream neurons moment by moment. Thus, this proposal will provide new molecular tools that will be used to establish a mechanistic link between dopamine release and movement.

Deborah Luessen, PhD

ASSISTANT PROFESSOR, SCHOOL OF MEDICINE, PEDIATRICS

Neurodevelopmental Dopamine D1 Receptor Regulation of Prefrontal–Accumbens Circuits in Cognition

Dopamine signaling in the prefrontal cortex (PFC) is critical for learning, memory, and executive function, in part by providing reward-prediction error signals that guide reward-based learning and gate task-relevant information in working memory. While dopamine D1 receptors (D1Rs) in the PFC are known to modulate neural activity during working memory, their role in the cellular mechanisms underlying learning across development remains poorly understood. Notably, excitatory PFC neurons projecting to the nucleus accumbens (NAc) exhibit elevated D1R expression during adolescence compared with pre-adolescent and adult stages. Preliminary data further demonstrate increased D1R sensitivity on these cortical projection neurons during adolescence, suggesting a developmentally regulated window of enhanced dopaminergic modulation. However, the functional consequences of this dynamic regulation for circuit activity and cognition are unknown.  This project will define the neurodevelopmental role of D1Rs on PFC–NAc corticostriatal projections during distinct phases of cognition. Using in vivo fiber photometry (GCaMP6m), I will longitudinally characterize activity of PFC–NAc excitatory projections in mice performing touchscreen-based working memory and cognitive flexibility tasks. In parallel, I will systematically evaluate D1R function within this circuit using targeted receptor pharmacology to determine how developmental changes in D1R sensitivity shape circuit dynamics and cognitive performance.  Together, these studies will provide mechanistic insight into how dopamine D1 receptor signaling within defined corticostriatal circuits supports the acquisition and maturation of complex cognitive processes. This

Wendy McKimpson, PhD

ASSISTANT PROFESSOR, SCHOOL OF MEDICINE, MEDICINE 

Treating type 2 diabetes by blocking an EMT-like program in pancreatic beta-cells

A critical contributor to type 2 diabetes (T2D) is the loss of insulin-secreting pancreatic beta-cells by dysfunction or loss of identity by dedifferentiation, although much remains unknown. beta-cells are derived from endoderm. We have identified some beta-cells activate an epithelial-to-mesenchymal(EMT)-like pathway during T2D. This program occurs in human and mice and is driven by upregulation of the cancer transcription factor Yap1. Further, beta-cell-specific deletion of Yap1 protects mice from developing diabetes and maintains beta-cell function. In data presented in this grant, we show that it is possible to use compounds to thwart EMT-like activation in primary mouse beta-cells by either inhibiting Yap1 or blocking the mesenchymal protein N-cadherin. It is not known whether similar targeting of EMT-like failure in mice will curtail diabetes. Thus, the purpose of this grant is to determine whether EMT-like beta-cells can be harnessed for a T2D therapy. We hypothesize that blocking EMT-like beta-cell failure will delay T2D onset during early stages of disease and restore beta-cell function and glucose sensitivity when targeted later. Accordingly, we will demonstrate that mice treated with the Yap1 inhibitor Verteporfin will have diminished onset of diabetes when fed a high fat diet (Aim1). We will also show that diabetic mice have improved metabolism when treated with ADH-1, a N-cadherin blocking antibody (Aim2). Innovation and significance lie in our targeting of a novel mode of beta-cell failure that we identified as well as developing T2D therapies that harness drugs currently used to treat other diseases.

Kristy Murray, DVM, PhD

PROFESSOR, SCHOOL OF MEDICINE, PEDIATRICS

Lighting Up Neuroinvasion: Establishing Zebrafish Models to Visualize West Nile Virus Neuroinvasion and Accelerate Antiviral Discovery

West Nile virus (WNV) is the most common mosquito borne virus in the United States. Infection can lead to serious complications such as swelling of the brain, long-term neurological issues, and death; however, there are currently no medications available to prevent or treat the disease. Developing treatments is challenging because drugs must cross the brain’s protective barrier, avoid viral resistance, and reduce harmful inflammation from infection. New research tools are needed to understand how WNV reaches the brain and to speed up the search for effective therapies. Zebrafish are small, transparent fish used in research. They serve as a promising cost-efficient platform that allows researchers to monitor infections in real time and rapidly test many potential treatments. While zebrafish infection models for other viruses which affect the central nervous system (CNS) exist, there is no zebrafish model for WNV infection. This project will build the first zebrafish based infection model for WNV to accelerate drug discovery and visualize how the virus invades the CNS. We will do this by (1) adapting established methods to infect zebrafish with related viruses; (2) determining the best way to infect zebrafish with WNV; and (3) screening promising treatments at scale. Together, these aims will generate essential data for future research on WNV drug development and how viruses cause disease in the CNS. Consistent with URC priorities, the project expands Dr. Murray’s program into early-stage therapeutic development while providing post-doctoral fellow Dr. Weimer with substantive training that supports her trajectory toward research independence in antiviral drug discovery.

Weibo Niu, PhD

ASSISTANT PROFESSOR, SCHOOL OF MEDICINE, PSYCHIATRY AND BEHAVIORAL SCIENCES

Deciphering the interplay of mTOR signaling and epigenetic dynamics in mediating microglial dysfunction in Tuberous Sclerosis Complex

Tuberous sclerosis complex (TSC) is a genetic disorder that causes neurologic pathology such as epilepsy, developmental disability, or neuropsychiatric disease. TSC is caused by heterozygous, inactivating mutations in the TSC1 or TSC2 genes that encode protein binding partners hamartin and tuberin. Recent studies have established a connection between microglia activation and cognitive impairment in TSC patients. Microglia are brain-residing immune cells that play the central role in brain development and inflammation. However, how microglial functions are impaired in TSC and how their dysfunction contributes to TSC remain largely unknown. In this project, we aim to utilize human iPSC-derived microglia (iMG) to elucidate the mechanisms underlying microglia dysfunction in TSC. Strikingly, our preliminary work identified that significantly elevated itaconate (ITA) levels in TSC iMG. ITA, an immuno-metabolite, modulates the inflammatory response by inhibiting ten-eleven translocation (TET) DNA dioxygenases and altering 5-hydroxymethylcytosine (5hmC) dynamics. Importantly, 5hmC plays a key role in regulating neuroinflammation in microglia. We hypothesize that ITA dysregulates epigenome dynamics associated with the inflammatory response in TSC microglia, affecting microglial function and neurodevelopment in TSC. In Aim1, we will delineate the DNA methylation/hydroxymethylation homeostasis associated with TSC iMG in response to inflammatory challenges. In Aim2, we will determine the role of mTOR activation in DNA methylation/hydroxymethylation dynamics associated with TSC iMG. The proposed experiments will not only advance our understanding of the pathological roles of microglia in TSC but also lead to identification of novel therapeutic targets, facilitating the development of new treatment strategies for TSC and other brain disorders.

Rachanna Oeur, PhD

INSTRUCTOR, SCHOOL OF MEDICINE, BIOMEDICAL ENGINEERING

Development of a Pendulum Impact System for Studying Traumatic Brain Injury in a Swine Model

Traumatic brain injury (TBI) results in heterogenous outcomes that are related to region-specific responses to mechanical stimulation or brain disruption. Surveillance reports from the Center for Disease Control have consistently identified direct head impacts as the primary mechanism of TBI. Gyrencephalic large animal models provide an opportune platform to study the effects of direct head impacts on region-specific neurofunctional deficits; however, there are currently no devices that accurately replicate this mechanism of injury. Existing large animal models rely on non-impact head rotations, blast injury, open-skull cortical impacts, or fluid percussion injuries, none of which simulate direct head impacts. The goal of this project is to develop a pendulum impact system that replicates key mechanical features of human TBI. One factor often overlooked on injury outcomes is impact stiffness. Reducing impact stiffness through head protection (e.g., helmets) is a fundamental intervention for TBI. Although this strategy has been effective at mitigating catastrophic injuries such as skull fractures, concussions rates have remained largely unaffected. We hypothesize that reductions in impact stiffness engage greater brain volumes and a broader range of regions during mechanical loading. This project aims to: 1) develop a novel pendulum impact system that replicates key mechanical features common to human head impact injury; and 2) use an established swine TBI model to investigate how changes in impact stiffness lead to region-specific neurofunctional deficits. Mapping regional deficits following TBI will provide a framework for developing targeted interventions and therapeutics and may also shed light on previously proposed concussion classification subtypes.

Devesh Pant, PhD

INSTRUCTOR, SCHOOL OF MEDICINE, CELL BIOLOGY

Preliminary data to support an NIH proposal investigating role of sphingolipids in ALS

Alterations in sphingolipid metabolism are increasingly recognized as contributors to neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). SPTLC1, encoding the long-chain base subunit of serine palmitoyltransferase (SPT), catalyzes the first and rate-limiting step in sphingolipid biosynthesis. Mutations in SPTLC1 have been linked to hereditary sensory and autonomic neuropathy type I (HSAN1) and juvenile ALS (jALS). These mutations disrupt the balance of sphingolipids, implicating sphingolipid dysregulation in motor neuron vulnerability. Despite these findings, the physiological role of SPTLC1 in the central nervous system (CNS) remains poorly defined, primarily because global Sptlc1 knockout mice are embryonically lethal due to complete loss of SPT activity. Our preliminary data demonstrate that homozygous deletion of Sptlc1 exon 2 (ΔE2)—which encodes a critical N-terminal transmembrane domain required for ER anchoring—causes early lethality and severe motor dysfunction, indicating its essential role in neuronal viability. Interestingly, our findings suggest that targeted exon 2 deletion produces a protein that retains partial localization and residual enzymatic activity in vivo, unlike the null phenotype of global Sptlc1 knockouts. This provides a tractable system to model partial SPT dysfunction, similar to what is observed in human ALS disease. Currently, there are no in vivo models that allow precise dissection of SPTLC1 function in the CNS. By creating the first conditional Sptlc1 ΔExon2 mouse, this project will reveal how disrupted sphingolipid homeostasis drives neurodegeneration and will establish a foundational tool to study metabolic mechanisms underlying ALS.

Janani Parameswaran, PhD

INSTRUCTOR, SCHOOL OF MEDICINE, CELL BIOLOGY

VCP-TMEM106B Axis as a cross-disease mechanism of neurodegeneration

Protein aggregation and impaired proteostasis are central features of neurodegenerative disease. TMEM106B, a lysosomal membrane protein, has recently been identified as a core component of pathological amyloid fibrils across multiple neurodegenerative disorders. Proteomic analyses of these fibrils reveal enrichment of protein quality control factors, including valosin-containing protein (VCP), a ubiquitin-dependent ATPase essential for protein clearance. However, the mechanisms regulating TMEM106B turnover, aggregation, and toxicity remain unknown. Our preliminary analysis of postmortem FTD brain tissue reveals an inverse relationship between VCP levels and TMEM106B fibril burden, suggesting that VCP dysfunction promotes TMEM106B accumulation.  This project will define how VCP regulates TMEM106B proteostasis and neurotoxicity using complementary human and in vivo models. In Aim 1, we will determine how VCP controls TMEM106B solubility, aggregation, and degradation pathways in iPSC-derived cortical neurons. In Aim 2, we will test VCP as a genetic modifier of TMEM106B-driven neurodegeneration using newly developed Drosophila models expressing human TMEM106B, which exhibit retinal degeneration and reduced lifespan. Together, these studies will reveal fundamental mechanisms governing TMEM106B proteostasis and identify VCP-dependent pathways as potential therapeutic targets in protein aggregation–associated neurodegenerative diseases.

Anupam Patgiri, PhD

ASSISTANT PROFESSOR, SCHOOL OF MEDICINE, PHARMACOLOGY AND CHEMICAL BIOLOGY

Harnessing Mitochondrial Recycling to Treat Childhood Mitochondrial Disease

Mitochondrial diseases are devastating childhood disorders caused by inherited genetic defects that disrupt the cell’s ability to produce energy. Each cell contains thousands of mitochondria, and patients carry a mixture of healthy and defective mitochondria; when defective mitochondria exceed a critical threshold, disease develops. These conditions affect ~1 in 4,000 children, and many affected children fail to thrive and do not survive beyond the first decade of life. There are currently no effective treatments, creating an urgent need for new therapeutic approaches. Healthy cells normally remove damaged mitochondria through mitophagy, the cell’s natural recycling system. In mitochondrial disease, this protective process can break down, allowing defective mitochondria to accumulate and generate toxic stress that further harms tissues. To address this problem, my lab has developed a new class of small-molecule drug candidates called Mitochondria-Targeted Autophagy Catalysts (MiTACs). MiTACs act like precision tools that “tag” damaged mitochondria for recycling, enabling cells to replace them with healthier ones. Because defective mitochondria are more vulnerable to mitophagy, MiTACs are designed to preferentially remove the most harmful mitochondria while sparing healthier ones. In preliminary studies, our lead candidate MiTAC2 restored mitochondrial recycling and improved mitochondrial health in aging muscle cells. In this project, we will test MiTAC2 in models of pediatric mitochondrial disease caused by mitochondrial DNA mutations and deletions. If successful, MiTAC2 could reduce the burden of defective mitochondria, promote the formation of new healthy mitochondria, and lay the groundwork for the first effective therapy for currently incurable childhood mitochondrial diseases.

Christopher Rodgers, PhD

ASSISTANT PROFESSOR, SCHOOL OF MEDICINE, NEUROSURGERY

Whole-body motor control by the motor cortex in a mouse model of Parkinson's disease

Parkinson’s Disease (PD) is characterized by neurodegeneration and progressive motor deficits. Our understanding of the fundamental processes that underlie PD is limited, in part because laboratory animals are normally tested on relatively simple motor behaviors. Our laboratory has expertise in developing complex behavioral assays for mice, recording large-scale neural activity in multiple brain regions, and using computational analysis to explain how behavior arises from neural dynamics. We have recently developed a new behavioral assay in which freely moving mice voluntarily exhibit varied and agile behavior. In this URC proposal, we will first quantify this agile behavior and examine how it changes over the progression of PD-like pathology in the MitoPark mouse, a genetic model of dopaminergic degeneration. Second, we will record large neural populations in the motor cortex to examine how their dynamics relate to behavior, and how these dynamics change in the MitoPark mouse. The motor cortex is an important therapeutic target because proven neurotechnology for interfacing with the motor cortex is already in use for other disorders, such as in brain-machine interfaces for paraplegia. The pilot study proposed here will lay the groundwork for a larger-scale project to develop neurotechnology that may restore normal function in MitoPark mice. Our long-term goal is to take what we have learned in mice and to collaborate with doctors and neurosurgeons to develop devices to halt the progression of PD in the brain and restore healthy function and quality of life.

Andrew Shafik, PhD

INSTRUCTOR, SCHOOL OF MEDICINE, HUMAN GENETICS

Elucidating the role of N6-methyladenosine in human Alzheimer's disease

Alzheimer’s disease (AD) is a brain disorder that slowly damages neurons, leading to memory loss and cognitive decline. Recently, emerging evidence suggested that a chemical modification of RNA called N6-methyladenosine (m6A) could affect AD pathogenesis. This small modification can help control how genes are turned into proteins, which is essential for healthy brain function. However, how m6A changes and the pathways affected by the dysregulation of m6A in AD is largely unknown in humans.  In this project, we aim to understand how the role of m6A in human AD. We will study human neurons that are directly converted from skin cells donated by well-characterized individuals, including healthy controls, and people with AD. Unlike other stem cell–based methods, this direct conversion preserves important features related to aging and disease, allowing us to better mimic what happens in the human brain. Using these neurons, we will measure both changes in m6A and gene activity from the same samples. We will compare results from the neurons to postmortem AD tissue as a validation. Furthermore, we will determine the functional impact of m6A in the neurons by removing proteins involved in m6A regulation and assessing neuronal function and viability.  Ultimately, this work will improve our understanding of AD at a molecular level. Our findings may help identify novel therapeutic targets aimed at restoring healthy RNA regulation in neurons.

Mala Shanmugam, PhD

ASSOCIATE PROFESSOR, SCHOOL OF MEDICINE, HMO

Targeting lipid-induced therapy resistance in multiple myeloma

Multiple myeloma (MM) is a fatal disease with 36,110 estimated diagnoses and 12,030 deaths in the US in 2025. MM exhibit founder genetic lesions and one sub group exhibiting the t(11;14) translocation are BCL-2 dependent and sensitive to BCL-2 antagonists like venetoclax (Ven). MM patients treated with Ven however relapse within ~11 months of treatment, underscoring the need to identify mechanisms of Ven resistance and drugs that can overcome resistance. Cancer cells alter cellular metabolism to support various processes including anti-apoptotic dependencies and proximity to the apoptotic threshold. MM cells reside in the bone marrow (BM) microenvironment. Adipocytes comprise 70% of the BM volume and are a source of fatty acids that support MM survival and proliferation and contribute to therapy resistance. Recently we determined that the most abundant BM fatty acid, oleic acid (OA) can promote resistance to Ven. Mechanistic interogation of the OA-induced kinome in MM identified activation of the c-JUN transcription factor, targeting of which restored sensitivity to Ven in the context of OA. To overcome OA induced Ven resistance we have implemented a high through put drug screen comprising 2036 diverse small molecules with validated biological and pharmacological activities, including 1018 FDA approved compounds in collaboration with the the Emory Chemical Biology Discovery Center. Our objective is to define the mechanistic basis of OA-induced Ven resistance and methods to overcome this resistance. Our findings will reveal biology and targetable vulnerabilities in the context of lipids that are critical to sustaining MM growth and therapy refractory disease.

Luyao Shen, PhD

INSTRUCTOR, SCHOOL OF MEDICINE, BIOMEDICAL ENGINEERING

DNA-based shear stress nanoreporter

Cells biologically respond to hydrodynamic forces induced by flow, However, it’s impossible to directly measure shear stress in complex anatomical sites such as the cardio, cerebral or tumor vasculature, and in smaller sites such as nephrons, mammary glands, or lymphatics. Existing in vivo approaches indirectly estimate shear from measurements of geometry and flow velocity and are hard to adapt to small, geometrically complex anatomical sites. The key barrier to progress has been the lack of direct, easy to use fluorescent reporters that measure the multiaxial and dynamic shear flows that occur in vitro and in vivo across an entire surface of interest. The goal of the current proposal is to create a DNA-based optical reporter of fluidic shear stress that can be attached to cell-lined or inorganic surfaces and quantitatively visualize the applied shear stress. Each DNA-based shear stress nanoreporter (DNA-SSNano), consists of an antibody-based anchor, a DNA based optical force transducer, and a mechanical amplifier. As flow is applied to this structure, the DNA hairpins unfold and fluoresce. Our approach has the potential to increase the speed and sensitivity of shear stress measurements in vivo in real time. This novel biosensor is a universal platform that can be applied in different biological regions where shear stress occurs. It can be adapted to other complex fluid dynamics (e.g., viscoelastic fluid) which currently no method can directly measure. This is also a modular sensor that can be tuned to measure other analytes (e.g. proteins, viruses etc.) with very high sensitivity.

Jenny Shim, MD

ASSISTANT PROFESSOR, SCHOOL OF MEDICINE, PEDIATRICS

Investigating YAP-mediated transcriptional regulation in relapsed/refractory neuroblastoma

My research focuses on neuroblastoma, which is the most common solid cancer that occurs outside of the brain/spine in young children. Neuroblastoma develops from early nerve cells of the peripheral nervous system. Children with the most aggressive form of neuroblastoma, high-risk neuroblastoma, undergo very intensive treatment. This often includes many rounds of chemotherapy, surgery, autologous stem cell transplants with high doses of chemotherapy, radiation, immunotherapy with additional biology therapy. Even with all of these treatments, only about half of these children are cured. Sadly, in many cases, the cancer comes back, and when it does, there is currently no cure. I am especially interested in understanding how and why some neuroblastoma cells are able to survive and how and why some neuroblastoma cells are able to return even after such intensive treatment. I have been investigating a protein called the Yes-Associated Protein or YAP, which has been linked to neuroblastoma that does not respond to initial treatment (refractory neuroblastoma) or to neuroblastoma that comes back after treatment (relapsed neuroblastoma). In this project, I aim to find new treatment combinations by learning how YAP helps cancer cells stay alive. YAP can shut off genes that would normally cause damaged or unhealthy cells to die. By understanding how this process occurs, we may be able to develop new combination of treatments that are better at killing these resistant neuroblastoma cells. My ultimate goal is to bring these discoveries into new treatments in the clinic for our children with relapsed/refractory neuroblastoma.

Stacey Smith, PhD

ASSISTANT PROFESSOR, SCHOOL OF MEDICINE, INFECTIOUS DISEASES

An ex vivo model to evaluate potential therapies for HIV-associated gut mucosal damage

Regardless of transmission route, the gut mucosal barrier sustains substantial structural and immunological damage during early HIV infection. Ongoing translocation of microbial products across this damaged gut barrier into systemic circulation is thought to be a major contributor to the persistent inflammation observed in persons with HIV (PWH), even with effective antiviral therapy. This chronic inflammation has been associated the development of non-AIDS comorbidities (NACM) in PWH, including metabolic, cardiovascular, and neurological diseases. Restoration of gut barrier structural integrity is therefore thought to be a critical therapeutic priority, with the goal of improving long-term health outcomes in PWH. However, progress towards this goal has been limited by the complexity and expense of animal studies and human clinical trials. Here, we will directly address the critical need for a human-based ex vivo model of the gut mucosal barrier, using primary intestinal stem cell-derived colonic organoids from heathy donors and PWH. Once established, this model barrier will be used to evaluate the efficacy of a candidate therapeutic (approved for use in Irritable Bowel Syndrome), Tofacitinib, to restore gut barrier integrity and reduce inflammation after induction of an inflammatory injury (IFN-g). The goal of this URC is to establish a model for evaluating personalized gut barrier treatment regimens for PWH ex vivo, with future applications expanding to address gut barrier dysfunction in normal healthy aging and other chronic inflammatory conditions. 

Meng Zhang, PhD

ASSISTANT PROFESSOR, SCHOOL OF MEDICINE, UROLOGY

Discovery of functional microproteins in prostate cancer

Despite effective treatments for localized prostate cancer (PCa), many patients progress to metastatic castration-resistant prostate cancer (mCRPC), the lethal stage of the disease. Current therapies extend survival by only a few months, underscoring an urgent need for new treatments for therapy-resistant advanced PCa. Microproteins – proteins under 100 amino acids – are emerging cancer drug targets. Functional screens showed that some are essential for cancer cell growth, and individual studies demonstrated their key molecular functions. Several biotech companies are developing microprotein-targeting therapies, yet they have not been systematically studied in PCa. Our analysis of RNA sequencing from benign prostate, localized PCa, and mCRPC, coupled with ribosome profiling in pre-clinical models, revealed widespread dysregulation and active translation of microproteins in mCRPC. We hypothesize that specific microproteins are critical for prostate tumor growth and may serve as novel drug targets. We propose two aims to discover novel functional microproteins in prostate cancer: Aim 1 will define the landscape of microproteins translation in PCa using proteomics; Aim 2 will identify functional microproteins required for advanced PCa growth using a CRISPR knockout screen targeting all annotated microproteins. Successful completion of this work will advance our understanding of PCa biology and nominate clinically actionable microproteins as new therapeutic targets for advanced PCa. These results will provide strong preliminary data for future funding opportunities, including DoD PCRP Idea Development Award, NIH-NCI R01, and foundation grants such as Prostate Cancer Foundation and V Foundation.

Shirley Zhang, PhD

ASSISTANT PROFESSOR, SCHOOL OF MEDICINE, CELL BIOLOGY

A Human Cell–Based Assay to Study Circadian Control of Chemotherapy Delivery Across the Blood–Brain Barrier

Brain cancer is difficult to treat because most chemotherapy drugs cannot effectively reach tumors in the brain. This is due to the blood–brain barrier (BBB), a protective layer of blood vessels that controls what enters the brain but also limits the success of many cancer therapies. Recent research shows that the BBB changes over the course of the day according to the body’s internal biological clock, known as circadian rhythms. These daily rhythms can influence how drugs move into and out of the brain, suggesting that the timing of chemotherapy may affect how well it works. In patients with glioblastoma, the most aggressive brain cancer, taking the chemotherapy drug temozolomide in the morning has been linked to improved survival. However, it is unknown whether other brain cancer drugs are affected in the same way. This project will develop and validate a laboratory-based model of the human blood–brain barrier to measure how time of day influences the delivery and effectiveness of chemotherapy drugs. Using this system, we will test a small group of commonly used brain cancer treatments to determine whether their ability to kill tumor cells depends on circadian timing. The results will provide a new tool to help optimize chemotherapy timing and may inform future strategies to improve brain cancer treatment.

Qi Zhang, PhD

ASSISTANT PROFESSOR, SCHOOL OF MEDICINE, PHARMACOLOGY AND CHEMICAL BIOLOGY

Targeting clusterin glycosylation in Alzheimer's disease

Alzheimer's disease (AD) is a complex neurological condition characterized by a gradual decline in cognitive abilities. Despite extensive research, the molecular mechanisms underlying AD remain incompletely understood, underscoring the urgent need to define pathogenic pathways and discover novel therapeutic targets. Clusterin (CLU) is the third most significant risk factor for Alzheimer's disease (AD) and is implicated in amyloid-beta (Aβ) clearance, neuroinflammation, and neuroprotection through chaperone and anti-apoptotic activities. CLU is highly glycosylated, and preliminary research suggests that CLU glycosylation affects its essential functions during AD progression. However, due to technological barriers, previous studies of glycosylation function in AD have been limited due to the inability to decipher the site-specific glycan composition. The proposed research targets this critical yet under-explored aspect of AD, focusing on investigating CLU glycoforms, including their dysregulation and their potential as novel early-stage biomarkers and molecular targets. We aim to overcome these limitations by comprehensively profiling CLU glycoforms using a cutting-edge immunoprecipitation-mass spectrometry (IP-MS)-based intact glycopeptide analysis technique, which has already shown promising performance in our preliminary experiments. This project has two primary objectives: to analyze CLU glycoforms from AD, mild cognitive impairment (MCI), and control brain specimens to uncover CLU glycoform underlying brain function in Alzheimer's disease and to identify blood-based CLU glycoform biomarkers for early diagnosis and monitoring of disease progression. Findings from the proposed research will advance our understanding of AD pathogenesis and provide novel targets for AD diagnostic and therapeutic development.

Jian Zhou, PhD

ASSISTANT PROFESSOR, SCHOOL OF MEDICINE, HUMAN GENETICS

Real-Time Visualization of Activity-Dependent Transcriptional Cascades in Autism

Precise control of activity-dependent transcription is fundamental to brain development, learning, and behavior. In response to neuronal stimulation, specific transcriptional programs are rapidly activated to shape synaptic connectivity and circuit function. Disruption of these programs is increasingly recognized as a hallmark of neurodevelopmental conditions, including autism spectrum disorder (ASD). Therefore, studying the dynamic regulation of activity-dependent transcription is essential for elucidating brain function and developing targeted therapeutic strategies for neurodevelopmental disorders. However, comprehensive exploration of activity-dependent transcriptional control in health and disease conditions, especially in live neurons, has remained challenging due to a dearth of suitable tools and disease model systems. My recent work has uncovered a previously unknown chromatin regulatory complex, the MeCP2–TCF20 complex, that is essential for proper activity-dependent gene activation. Pathogenic mutations found in patients with ASD-like phenotypes selectively impair the assembly of this complex, providing an ideal paradigm to dissect the causal link between defective stimulus-induced transcription and ASD pathogenesis. My proposal seeks to combine innovative single-molecule imaging and in situ spatial transcriptomics in sophisticated disease models to directly visualize how neuronal activity assembles the MeCP2–TCF20 complex on chromatin to drive proper gene regulation, and how this critical process is disrupted in disease. By linking molecular mechanisms to real-time cell activity, this work could finally tackle the challenge of studying the relevant biochemistry and molecular biology directly in their native environment within live cells, rather than in test tubes.