Biological and Health Sciences

Jimena Andersen, PhD

Assistant Professor, School Of Medicine, Human Genetics

Investigating neuron-OPC interactions in a 3D human model of the spinal cord

Oligodendrocyte progenitor cells (OPCs) can respond to demyelinating injury by differentiating into new myelinating oligodendrocytes. Neuronal activity has emerged as an important factor modulating OPC proliferation, migration and differentiation. However, the precise nature of neuron-OPC interactions in the spinal cord is not known. Understanding how neurons in the spinal cord regulate OPC behavior is a key step in promoting remyelination in disease conditions.We previously described cortico-motor assembloids, a human induced pluripotent stem cell (hiPSC)-derived platform to study cell-cell interactions in the cortico-motor pathway. Our recent preliminary data suggests that cortico-motor assembloids are a powerful model to study neuron-OPC interactions. Based on this work, we hypothesize that neurotransmitter signaling modulates OPC differentiation and myelination in the human spinal cord through specific neuron-OPC interactions. Here, we aim to dissect the role of these neuron-OPC interactions. We will use a combination of optogenetics, pharmacology and monosynaptically-restricted rabies virus tracing to pinpoint relevant interactions. Specifically, we will 1) investigate the role of glutamate, GABA and acetylcholine in OPC proliferation, differentiation and myelination, and 2) map in vitro spinal cord OPC connectivity. Altogether, this work will highlight neuronal mechanisms that could be leveraged to promote remyelination in the future.

Byron Au-Yeung, PhD

Assistant Professor, School Of Medicine, Immunology Medicine

Identification of a subpopulation of naive T cells with increased colitogenic potential in human and mice

Inflammatory Bowel Disease (IBD) encompasses Ulcerative Colitis and Crohn’s Disease, conditions characterized by chronic inflammation of the gastrointestinal tract. Genetic studies and animal models strongly suggest that T cells, one type of adaptive immune cell, promotes the inflammatory immune responses that occur in IBD. However, T cells are a functionally diverse population of cells and it is still unclear which T cells are responsible for initiating the immune responses that lead to the development of IBD. Our preliminary studies were the first to identify two types of “helper” T cells with the use of genetically modified mouse models. We found that Population “A” appears to induce a severe form of colitis and Population “D” induces much less severe colitis, in a mouse model of IBD. In this proposal, we aim to better understand the functional properties of Population “A” and “D” cells from mice and humans. We hypothesize that Population “A” cells are a hyperactive cell type, whereas Population “D” cells are protective. We plan to isolate, then compare the behaviors of Population “A” and “D” cells to better understand how each promotes immune responses. We propose that the functions of “A” and “D” cells are balanced in a healthy immune response and that tipping the balance toward Population “A” function could increase the susceptibility to IBD. These studies will provide a framework for understanding of two types of helper T cells that are not well characterized, and their potential relationship to the chronic inflammatory immune responses in IBD.

Christopher Beck, PhD

Professor Of Pedagogy, Practice Or Performance, Emory College Of Arts And Sciences, Biology

Development of Student Science Identity in Introductory Biology

The degree to which students identify as scientists (science identity) is known to impact persistence in the sciences. As a result, gaining a more complete understanding of the development of student science identity, especially in introductory science courses, is important. In a previous study across our two-semester, introductory biology sequence at Emory, we found that students begin with intermediate science identity that increases during the first semester and only increases very slightly during the second semester. Our previous work and that of others have collected data on coarse timescales (i.e., beginning of the semester as compared to end of the semester), but the dynamics of science identity within a semester is unclear. As a result, the overall goal of this proof-of-concept study is to explore the potential of using short surveys delivered by text message every other week to examine variation in and change in science identity throughout a semester of introductory biology. By collecting data on shorter time intervals throughout a semester of introductory biology, the proposed study will address the following specific questions: (1) how much does science identity vary within a semester; (2) how does science identity change over time; and (3) what factors might lead to changes in science identity. The preliminary data collected in this study would be used as the basis of a proposal to the National Science Foundation to study the development of science identity across introductory science courses at Emory or in introductory biology courses at other universities with different student demographics.

Victor Faundez, PhD

Professor, School Of Medicine, Cell Biology

Mitochondrial Alzheimer's Disease Risk Loci Control APOE Gene Expression

This proposal focuses on a pathway where genetic defects affecting mitochondria result in an upregulation of the secreted factor apolipoprotein E (APOE). The APOE E4 allele (APOE4) is the main genetic risk factor for Alzheimer’s disease. Thus, mechanisms controlling the expression of APOE may be paramount to the pathogenesis of Alzheimer’s disease. We posit that disruption of the respiratory chain modulates the expression of APOE. This model is based on our observation that genetic disruption of the electron transport chain increases the expression and secretion of APOE up to 49-fold. The relevance of this pathwat to disease is highlighted by the fact that mutation of two genes required for normal complex I respiratory function, NDUFS3 and NDUFAF7, result in large increases in APOE secretion. These two genes encode mitochondrial proteins that belong to novel and robust Alzheimer’s disease genetic risk loci. The significance and impact of our model stems the integration of four genetic risk factors for Alzheimer’s disease (APOE, NDUFS3, NDUFAF7, and COX7C) with age into a novel mechanism where mitochondrial dysfunction is the most upstream step. By doing so, we upend current canonical views that mitochondrial dysfunction is merely a terminal event in Alzheimer’s disease. Rather, we propose that mitochondrial defects by itself could drive APOE-dependent pathology and disease progression/severity. Here we will test the hypothesis that dysfunction of the respiratory chain upregulates APOE expression as a protective mechanism using iPSC-derived human neurons and astrocytes carrying APOE alleles that modify the risk of Alzheimer’s.

Shannon Gourley, PhD

Associate Professor, National Primate Research Center

Mechanisms supporting the development and reliance on habitual routines in young organisms

Habits are familiar, routinized behaviors triggered by cues in the environment. Young children are experts in habitual behaviors – they learn routines rapidly, and readily link them to external stimuli like the time of day (for instance, a bedtime routine). What remains poorly understood, however, are the neural mechanisms that endow young children with such proficiency in establishing and adhering to habits. New knowledge could be enormously helpful in understanding why some neurodevelopmental illnesses like autism spectrum disorders (ASD) are characterized by aberrant behavioral rigidity and habit compliance. Routines take on greater-than-typical salience, and their violation is distressful. These qualities create perpetuating and self-reinforcing cycles of behavior that imperil the quality of life of children with ASD and their caregivers.

In Aim 1, we will test the hypothesis that ventral hippocampal (vHC)-to-central nucleus of the amygdala connections stabilize early in life and are necessary for habitual action in young, typically developing mice. In Aim 2, we will selectively delete 2 high confidence ASD risk genes, Chd8, encoding Chromodomain helicase domain 8, and Syngap1, encoding Synaptic Ras GTPase activating protein 1, in excitatory neurons in the developing vHC. We will test the hypothesis that gene deletion will induce over-adherence to habits and trigger markers of neuron hyper-excitability. We will then use combinatorial viral vector strategies to simultaneously dampen the excitability of vHC neurons to mitigate habit biases. Positive outcomes would suggest that vHC hyper-excitability is a common mechanism by which mutations with distinct molecular consequences induce over-reliance on routines in ASD.

Seong Su Kang, PhD

Assistant Professor, School Of Medicine, Medicine, Pathology And Laboratory Medicine

BDNF/C/EBPβ axis regulates the major pathogenesis in Alzheimer’s Disease

Alzheimer's disease (AD) is characterized by the accumulation of the β-amyloid peptide (Aβ) and phosphorylated or cleaved forms of the microtubule-associated protein Tau (MAPT), in addition to chronic neuro-inflammation. It has been well known that BDNF (brain-derived neurotrophic factor) has a protective role against AD pathogenesis as well as neuronal survival. However, its molecular mechanism related to the inhibition of AD is not clear. C/EBPβ (CCAAT-enhancer Binding Protein-β) is induced by pro-inflammatory cytokines that are chronically upregulated in AD brain. In our preliminary study, we found that BDNF deprivation upregulates C/EBPβ, correlating with the upregulation of delta-secretase, which is asparagine endopeptidase (AEP, LGMN) and cleaves both amyloid-beta precursor protein (APP) and Tau in the aged brains and human AD. Moreover, delta-secretase is regulated by C/EBPβ during the aging process and depletion of delta-secretase substantially abolishes senile plaques in AD mouse model expressing 5 familial AD mutations (5xFAD), and neurofibrillary tangles (NFT) in Tau P301S AD mice expressing mutant human MAPT, leading to prominent restoration of synaptic plasticity and cognitive functions. Therefore, we presume that BDNF/C/EBPβ axis may play a critical role in AD pathogenesis and progression during aging. The objective of this proposal is to test the hypothesis that BDNF/C/EBPβ axis regulates all of the major pathogenesis including senile plaque, NFT, and neuro-inflammation in AD via regulating delta-secretase expression. Successful completion of the proposed study will lead to the identification of a novel drug target for treatment of AD.

Aubrey Kelly, PhD

Assistant Professor, Emory College Of Arts And Sciences, Psychology

Oxytocin-Mediated Newcomer Acceptance Into An Established Group

A sense of belonging is crucial to human health and having a weak tie to a community or failing to become accepted into a group results in a deterioration in physical and mental health or even directed violence toward the exclusive group. How do we successfully join new groups? Here I propose to use the highly prosocial spiny mouse to examine behavioral and neural correlates that enable individuals to successfully integrate into a community. I will (1) identify behavioral patterns that enable a newcomer to successfully join a new group and (2) use [wired] fiber photometry to determine how oxytocin modulates social learning that facilitates those behaviors. Additionally, I will validate a highly innovative new tool in spiny mice – wireless fiber photometry. This will allow us to conduct studies examining the neuroscience of collective mammalian group behavior in an unprecedented manner. This proposal will specifically examine the brain and behavior of the newcomer; however, this data will serve as preliminary data for an NIH grant that will propose to examine not only the brain and behavior of the newcomer, but also the brain/behavior of all members of the group. Identifying behavioral and underlying neural mechanisms that promote group acceptance and stability will not only help us develop behavioral strategies that can promote the establishment and stabilization of our own communities, but also behavioral and possibly even neural therapies that could help individuals who struggle to fit in and acquire a sense of belonging.

Rebecca Levit, PhD

Assistant Professor, School Of Medicine, Medicine

Very early drivers of neutrophilic inflammation in cardiac ischemia-reperfusion

The immune system profoundly influences the recovery of the heart after myocardial infarction (MI). This is especially true in the modern era where the standard of care is reperfusion, which not only re-supplies tissue with oxygen and nutrients, but also delivers innate and adaptive immune cells to the myocardium. In humans, neutrophils are the most common white blood cell (WBC) in circulation and rapidly infiltrate the heart after reperfusion. Neutrophils can directly damage the heart as well as influence downstream inflammatory events. We performed single cell RNA sequencing of neutrophils 24 hours after reperfusion in mice. We identified a unique population of neutrophils with a gene signature responding to type I interferons (IFN-I). IFN-I are cytokines best known for activating the anti-viral immune response by binding to the type I IFN α and β receptor (IFNAR) leading to transcription of hundreds of downstream ‘interferon sensitive genes’ (ISGs). Previous studies have investigated the IFN-I response in MI using global knockout mice or chemical inhibitors, implicating macrophages as key responding cells. But the global nature of the models may have missed the role of neutrophils (1-3). The overarching hypothesis of this proposal is: Neutrophil response to IFN-I is a key early driver of neutrophilic inflammation culminating in impaired cardiac function after MI/R. In this proposal we will study mice with neutrophil-specific knock down of IFNAR. We will evaluate their functional recovery after MI/R and downstream inflammatory events to explore this as a neutrophil-targeted therapy after MI/R.

Cheryl Maier, PhD

Assistant Professor, School Of Medicine, Pathology And Laboratory Medicine

Defining the Impact of Therapeutic Plasma Exchange on COVID-19 via Plasma Proteomics

Despite tremendous strides in preventing severe COVID-19 through vaccines and antivirals, strategies for managing critical illness in those patients who nevertheless develop severe COVID-19 remain insufficient, largely due to limited understanding of the mechanisms driving systemic endotheliopathy and microvascular thrombosis that lead to organ failure and death. We previously reported increased blood viscosity from elevated fibrinogen in critically ill COVID-19 patients that was associated with disease severity and thrombosis, which led to the development of COPLEX, a small, non-funded randomized control trial investigating the use of therapeutic plasma exchange (TPE) to decrease fibrinogen levels and correct blood viscosity. Patients receiving TPE demonstrated significant normalization in a multitude of laboratory and clinical parameters and a lower incidence of death, and plasma samples were banked for later study. Separate mechanistic studies have recently uncovered a pathologic role of fibrinogen in promoting red blood cell aggregation that causes endothelial glycocalyx degradation in COVID-19. Thus, TPE may provide benefit in COVID-19 not only by decreasing blood viscosity but by restoring the biophysical properties of its cellular constituents, which will be reflected in plasma proteomic profiles. Here we propose to define the proteomic alterations in COVID-19 patient plasma following TPE and to determine any association between identified analytes with clinical and sociodemographic attributes already available in our COPLEX REDCap database. To our knowledge, this will be the first untargeted proteomic characterization of patient plasma after TPE in any patient population, thus providing data relevant to a variety of diseases for which this intervention is used.

Malavika Murugan, PhD

Assistant Professor, Emory College Of Arts And Sciences, Biology

Understanding the role of excitation/inhibition balance in regulating reward representations in the medial prefrontal cortex of CNTNAP2-/- mice

In the last 20 years, the number of children diagnosed with autism has grown by 175%. Today, 1 out of 100 children worldwide is diagnosed with autism. One of the main challenges people with autism face is difficulty with social interactions. Studies suggest that this is caused by an impaired ability to enjoy social interactions and find them rewarding. Evidence suggests changes in the brain's reward processing system might underlie these behavioral differences observed with autism. Specifically, there may be an imbalance in the way neurons in the medial prefrontal cortex communicate with each other in rewarding contexts. However, the mechanisms through which circuit-level changes in the mPFC relate to altered social behavior in people with autism remain poorly understood. The goal of this proposal is to understand how the brain processes reward in a mouse model of autism. In Aim 1 of this proposal, we will investigate the extent of similarities and differences in the reward representation between social and non-social reward in the excitatory and inhibitory neuron populations in the mPFC of CNTNAP2-/- and wildtype using cellular resolution calcium imaging performed in a transgenic mouse model. In Aim 2, we will design an integrate-and-fire network model of the mPFC capable of replicating the response profile observed in Aim 1, and modify the network properties to simulate an autism-like connectivity. Thus, this proposal will provide mechanistic insight into the circuit-level properties that lead to altered reward representations in mouse models of autism.

Donald Noble, PhD

Instructor, School Of Medicine, Cell Biology

Respiratory rate conditioning for pain control after spinal cord injury

Up to 70% of spinal cord injury (SCI) patients experience pain, yet there is no cure and pharmacological manipulations are often inadequate, only slightly reducing pain intensity. Both SCI and the ensuing pain are associated with respiratory complications including increased respiratory rate (RR), which in many conditions is associated with worsened clinical prognosis. As a fundamental physiological variable that can be voluntarily regulated, breathing has tremendous untapped potential as both a therapeutic intervention target, and a predictor of clinical outcomes in pain research. Strong evidence in humans suggests slowing breathing reduces pain; however, a mechanistic understanding of how this occurs is hindered by a lack of physiologically accurate, clinically-translatable animal models. To fill this gap in knowledge, using a one-of-a-kind rodent model and innovative monitoring technology, we showed that rodents could learn to slow RR (sRR) by operant conditioning, and sRR prevented development of hypersensitivity in an inflammatory pain model. In rats and mice, we also recently found respiratory abnormalities after SCI, including acutely increased rate and variability of breathing. Furthermore, truncal mechanical stimulation evoked increases in RR at chronic time points following SCI but not sham surgery, and acute increases in resting RR predicted the development of mechanical hypersensitivity. Building on these results, proposed studies investigate (i) trained slow RR as a strategy to block or reduce pain, and (ii) the reversibility of evoked pain activity in key neural circuits with sRR or chemogenetics. We envision studies leading to clinical uptake of wearable sRR technologies and enhancing pain management.

Shoichiro Ono, PhD

Associate Professor, School Of Medicine, Pathology And Laboratory Medicine

Functional analysis of coronin in assembly of muscle contractile apparatuses

Contractile forces produced by muscle tissues are essential for vital activities of animals, including humans, such as body movement, respiration, blood circulation, and food digestion. The biochemical basis of muscle contraction is the interaction between actin and myosin, which generates mechanical forces. For proper function of muscle, actin and myosin, together with many accessory components, need to be assembled into highly ordered contractile apparatuses, such that the actin-myosin interaction is tightly regulated to produce contractile forces in an efficient manner. Defective assembly of muscle contractile apparatuses can cause severe diseases in skeletal or cardiac muscles. However, the assembly mechanism of the contractile apparatuses is largely unknown. Our laboratory primarily investigates the regulatory mechanism of actin dynamics in muscle using genetics and cell biology in the nematode Caenorhabditis elegans and biochemistry using pure proteins. C. elegans is an excellent model organism for muscle cell biology because their body wall muscles share structural similarities with mammalian skeletal and cardiac muscles. By combining biochemical approaches, we have identified several key regulators of actin dynamics and gained insight into the conserved mechanism of actin regulation during assembly and maintenance of the muscle contractile apparatuses. In this URC project, we propose to characterize functions of coronin as a new actin regulator in muscle. Preliminary data suggest that a coronin gene is highly expressed in muscle and essential for muscle function in C. elegans. Results from this URC project should help us to strengthen the premise for applications to extramural funding.

Nisha Raj, PhD

Assistant Professor, School Of Medicine, Human Genetics

Interrogating neurogenic defects in complex assembloid models of fragile X syndrome

Since the discovery of the causal mutation in FMR1, enormous strides have been made in understanding fragile X syndrome (FXS), however, an effective treatment for the disorder is still lacking. We believe that a major gap in the preclinical phase may have been the lack of a developmentally relevant, physiologically representative human neuronal model. This proposal aims to address this by providing a human cellular platform with robust cellular and molecular readouts to test the efficacy of therapeutic interventions in FXS. We will use patient-derived induced pluripotent stem cells (iPSCs) that we can differentiate into organoids, which are 3D cultures of neural cells that recapitulate several features of human brain development in a dish. This technology provides an unprecedented opportunity to model human neurological disorders and potentially develop patient-specific therapeutics. Here, we propose to employ a novel assembloid system to study cell fate commitment of excitatory and inhibitory neurons as well as interneuron migration in FXS (Aim 1). We will further use organoids to determine the corrective effects of targeting the microtubule-associated cytoskeletal protein doublecortin (DCX), which is an mRNA target of FMRP as well as a downstream target of the cAMP intracellular cascade, which is compromised in FXS (Aim 2). These findings will provide critical insight into the underlying pathomechanisms in FXS, as well as into the biology of FMRP during early human development. Ultimately, this may aid in the development of targeted patient-specific therapeutic strategies that have broader implications for other neurodevelopmental disorders.

Patricia Zerra, MD

Assistant Professor, School Of Medicine, Pathology And Laboratory Medicine

IgM drives factor VIII-specific CD4 T cell proliferation in mice with hemophilia A

Roughly 20-30% of patients with severe hemophilia A develop neutralizing anti-factor VIII (FVIII) antibodies, known as inhibitors, following the administration of FVIII. Once a patient develops inhibitors their therapeutic options are limited, and there is an increased risk of morbidity and mortality1-10. Our failure to predict and prevent inhibitor formation largely stems from a fundamental lack of understanding about the key immune pathways that initiate this process. The goal of the proposed work is thus to identify key initiating immune factors that regulate anti-FVIII antibody formation, which will allow us to understand the underlying immune response to FVIII and then prevent this process in at-risk patients.

Using a pre-clinical model, we have identified marginal zone (MZ) B cells as a key initiating immune population in inhibitor development. Our current research aims to determine mechanisms by which MZ B cell contribute to propagation of the immune response to FVIII. Specifically, we aim to define the mechanisms by which IgM antibodies generated by MZ B cells facilitate T cell activation and proliferation. To do this, we will examine the immune response to FVIII in mice that lack IgM antibodies as well as the impact of anti-FVIII IgM antibodies on the localization of infused FVIII in the spleen of mice with hemophilia A.

The overall impact of this work will be to provide new insight into key aspects of inhibitor formation as well as an important framework to develop rational approaches to prevent inhibitor development following FVIII infusion in patients with hemophilia A.