Biological and Health Sciences
Bindu Chandrasekharan, PhD
INSTRUCTOR, SCHOOL OF MEDICINE, PATHOLOGY AND LABORATORY MEDICINE
Probiotics to Alleviate Gastrointestinal Disorders in the Offspring Induced by Maternal Antibiotics During Pregnancy
Early developmental periods (fetal and early postnatal) are a critical window of stress sensitivity that affects gut and brain functions. Maternal dysbiosis adversely affects gut physiology, fetal and postnatal enteric nervous system (ENS) development and induces gastrointestinal (GI) motility disorders. Though not recommended during pregnancy, pregnant women with gut dysfunctions (IBS or IBD) may require treatment with antibiotics. Antibiotic-induced dysbiosis causes increase in colonic bacteria like Bacteroides and Clostridium with reduction in Bifidobacterium. Our published studies demonstrate that probiotic beneficial microbes (Lactobacillus rhamnosus GG or LGG) can activate signaling in the enteric nerves in normal healthy mice and facilitate bowel movements. We demonstrated that activation of formylated peptide receptors (FPRs) is necessary and essential for the beneficial effects of probiotics like LGG on GI motility. Our recent preliminary data indicates that mouse pups derived from dams treated with antibiotics exhibit reduced neuronal density in the gut and reduced gut motility at 3 and 5 weeks of age. Based on these findings, we hypothesize that maternal probiotics can alleviate the adverse impacts of antibiotics on fetal and postnatal ENS development and GI motility. We will determine the role of FPR1/2 signaling on ENS development and GI motility as regulated by maternal antibiotics (Aim 1), and (b) explore the therapeutic role and the mechanisms by which probiotic LGG exerts protective effects focusing on FPR signaling (Aim 2). Thus, our studies will explore a probiotic-based approach to treat maternal antibiotic-induced gut disorders in the offspring which has high translational relevance.
Melissa Gilbert-Ross, PhD
ASSISTANT PROFESSOR, SCHOOL OF MEDICINE, HEMATOLOGY AND MEDICAL ONCOLOGY
Investigating the Function of PER1 in LKB1- Mutant Lung Cancer
Lung cancer is the leading cause of cancer-related deaths in both men and women. Despite knowledge of sex differences in lung cancer, the effect of sex as a biological variable has not been well-studied in lung cancer. LKB1 is frequently inactivated in lung cancer by mutations that segregate with oncogenic KRAS (KL subtype). Furthermore, LKB1 mutations are more frequent in males and are associated with worse overall survival in male, but not in female, patients. We analyzed expression of genes controlling circadian rhythm in our panel of female-derived human bronchial epithelial cells (HBECs) and found that expression of PER1 and PER2 are increased in LKB1-mutant lung cells. At the protein level, our results suggest that PER1 is differentially regulated in LKB1- mutant cells and in male and female mouse tumors. These data have led to our central hypothesis that LKB1 mutations alter PER1 activity to control circadian rhythm and contribute to sex differences in lung cancer incidence and progression. We aim to establish an interaction between biological sex, PER1 expression, and circadian rhythm signaling in vivo using male and female cell lines derived from our lab’s genetically engineered KL mouse model. In Aim 1A, we will establish sex-dependent differences in outcomes and circadian clock gene expression in a syngeneic mouse model of KL LUAD. In Aim 1B, we will investigate the mechanistic link between altered hormone signaling and loss of LKB1 in promoting lung tumor progression, providing preliminary data to develop a testable model for future external applications.
David R. Goldsmith, MD, MSc
ASSISTANT PROFESSOR, SCHOOL OF MEDICINE, PSYCHIATRY AND BEHAVIORAL SCIENCES
Targeting Inflammation-Induced Changes in Brain Reward Signaling in Patients with Schizophrenia and Negative Symptoms: A Pilot Study
Schizophrenia is a major public health concern, accounting for a high degree of morbidity and mortality and high costs to the healthcare system. Negative symptoms of schizophrenia refer to symptoms that are in deficit and include motivational deficits, which are some of the most debilitating aspects of the disorder, representing a significant barrier to functional recovery. Importantly, no medications treat negative symptoms. One pathophysiologic pathway that may contribute to these symptoms is inflammation. My published work has demonstrating associations between the inflammatory marker tumor necrosis factor (TNF) and negative symptoms of schizophrenia. My preliminary data demonstrates that inflammation is associated with motivational deficits. Higher concentrations of TNF are associated with lower signaling in the ventral striatum in response to reward as well as increased signaling in the anterior insula in response to effort. Both brain regions have been implicated in reward processing and may also be sensitive to inflammation. Demonstrating a causal relationship between inflammation and negative symptoms is the only way to begin to understand mechanisms underlying these devastating symptoms and begin to develop new treatments. To accomplish this goal, this proposal seeks to randomize individuals with schizophrenia with evidence of high inflammation and high negative symptoms to infusions of the TNF-blocker infliximab or placebo. I will measure brain signaling in neuroimaging tasks in addition to negative symptom assessments pre/post infusion. I hypothesize that individuals who receive infliximab (versus placebo) will have improvements in brain signaling as well as in behavioral and clinical measures of motivation and negative symptoms.
William H. Kitchens Jr., MD, PhD, FACS
ASSISTANT PROFESSOR, SCHOOL OF MEDICINE, TRANSPLANT CENTER
Impact of Chronic Heavy Alcohol Use on Alloresponses and Protective Immunity in Transplant Recipients
Alcoholic liver disease is now the leading indication for liver transplantation in the United States. The traditional requirement that patients maintain sobriety for at least six months prior to transplantation has recently been challenged, both at our transplant center and nationwide. An increasing proportion of our patients therefore have recent heavy alcohol consumption at the time of transplant. Importantly, chronic alcohol consumption is known to have myriad significant effects on the immune system, but its impact on organ transplant rejection is relatively uncharacterized. We therefore performed pilot experiments in which mice receiving skin grafts were fed alcohol chronically. Compared to similar mice that consumed water alone, the alcohol-treated mice demonstrated delayed transplant rejection. This unexpected result, which we also verified in other mouse skin graft models, suggests that chronic alcohol use may induce a state of relative immunosuppression, protecting organs from rejection but also potentially leaving transplant recipients at heightened risk of opportunistic infection. These intriguing findings have significant clinical relevance, suggesting that transplant recipients with recent heavy alcohol use might require lower doses of anti-rejection medications. Through a series of experiments, we intend to probe further the impact of alcohol on transplant rejection, examining whether alcohol use prolongs survival of transplanted liver cells in mice, whether chronic alcohol use indeed suppresses protective immunity against transplant-relevant pathogens, characterizing the cellular mechanisms that underpin the prolongation of transplant survival caused by alcohol, and (most importantly) examining whether this same immunodeviation from chronic alcohol exposure also occurs in human liver transplant recipients.
Sumin Kang, PhD
ASSOCIATE PROFESSOR, SCHOOL OF MEDICINE, HEMATOLOGY AND MEDICAL ONCOLOGY
Dissecting Pemetrexed Resistance in Non-Small Cell Lung Carcinoma
Despite the existence of various therapeutic approaches, chemotherapy is a mainstay of cancer treatment. Pemetrexed-based chemotherapy, which targets folate metabolism, is extensively used to treat non-small cell lung carcinoma (NSCLC), the most common type of lung cancer. However, patients often relapse due to the development of resistance, leading to therapeutic failure. Many studies have investigated possible chemoresistance models, yet the precise mechanism is still largely elusive. Protein kinases are well implicated in human cancers. To better understand the link between kinase-mediated metabolic regulation and pemetrexed resistance, we performed customized gene silencing to screen for a clinically-applicable target kinase that is critical for pemetrexed resistance. We found that inhibition of the fibroblast growth factor receptor (FGFR) family selectively sensitizes NSCLC cells to pemetrexed, leading to cancer cell death. This suggests that FGFR is a promising therapeutic target to improve the pemetrexed response. Protein profiling suggested that NSCLC cells may become pemetrexed resistant by FGFR modulating metabolic enzymes in folate metabolism or through factors in the MAPK pathway. In this proposal, we will explore how FGFR governs metabolic and survival signaling to cause pemetrexed resistance as well as investigate which FGFR inhibitors in combination with pemetrexed can stop or at least slow down the proliferation speed of tumors derived from NSCLC patients in mice. This proposal will not only provide information about the role of FGFR in pemetrexed resistance but also provide a new actionable approach to improve the treatment outcome of lung cancer that is not responsive to pemetrexed therapy.
Sohail Khoshnevis, PhD
ASSISTANT PROFESSOR, SCHOOL OF MEDICINE, BIOCHEMISTRY
Translational Control of Virulence Genes Expression During Cell Type Switching in Human Fungal Pathogen Candida Albicans
Candida albicans, an opportunistic fungal human pathogen, is responsible for ~700,000 cases of severe infections per year with 40% mortality rate. C. albicans can undergo a morphological transition from yeast to hyphae and this transition is central to C. albicans virulence. While transcriptional regulatory steps that are key for expression of virulence-related genes during cell-type switching in C. albicans have been studied extensively, the translational regulation aspects of this process are incompletely understood. The overall goal of this proposal is to investigate the role of translational control in regulating the expression of genes important for cell-type switching and virulence in Candida. To address this question, we focus on translation initiation, one of the most critical aspects of translation regulation, and the role of eukaryotic initiation factor 3 (eIF3) complex, the master regulator of translation initiation. The divergent composition of eIF3 complex between different organisms offers a unique opportunity for identifying new therapeutic targets to combat human pathogens. This proposal builds on our exciting novel preliminary data which reveal distinct compositional features of Candida eIF3 and define genes in C. albicans important for virulence that are regulated translationally during morphological transition. Here, we will test the hypothesis that Candida eIF3 regulates translation of genes important for pathogenicity during cell-type switching via a mechanism that is distinct from that of humans. Our results will reveal fundamental mechanisms of translation regulation in Candida albicans and how it impacts pathogenicity.
Chaoran Li, PhD
ASSISTANT PROFESSOR, SCHOOL OF MEDICINE, MEDICINE, MICROBIOLOGY AND IMMUNOLOGY
The role of PPARg+ skin regulatory T cells in controlling inflammatory skin diseases
Obesity is a major public health burden in the U.S. Recent studies show that Obesity is strongly associated with increased risk and severity of many inflammatory skin conditions, especially psoriasis, but the underlying mechanisms are still largely unclear. While many studies have focused on the regulation of immune cells that promote skin inflammation, the signals and factors that control the skin-resident immune subsets suppressing inflammation and how these anti-inflammatory cells might be disrupted in obese individuals that leads to worsened psoriasis are much less studied. We have recently identified that a unique subset of anti-inflammatory cells named regulatory T cells (Tregs) expressing the transcription factor PPARg+ reside in the skin and suppress psoriasis by limiting the level of IL-17, a key cytokine that drives psoriasis. However, these PPARg+ Tregs were drastically lost during obesity. The overall goal of this project is to dissect how PPARg+ skin Tregs suppress IL-17-driven psoriasis and whether their loss contributes to the increased risk/severity of psoriasis in obese individuals. This study should help to develop novel strategies to target PPARg+ skin Tregs to treat psoriasis, especially in obese patients.
Joseph Manns, PhD
ASSOCIATE PROFESSOR, ECAS, PSYCHOLOGY
Memory Prioritization Via Interactions Between the Amygdala and Hippocampus
Emotionally arousing events tend to be remembered better than nonemotional events, an evolutionarily adaptive prioritization of memory for important information. Two brain areas, the hippocampus and the basolateral amygdala, are key for this boost to memory. These brain areas are anatomically similar in humans and rodents, and much of what we know about emotional memories comes from experiments with rats. This past work has shown that the hippocampus is essential for remembering events, both emotional and nonemotional events. These studies have also shown that the basolateral amygdala is essential for enhancing memory of emotional events above that of nonemotional events. What has been missing from these past studies is fundamental data regarding how brain cells, or neurons, in the basolateral amygdala and hippocampus communicate with one another in real time to make a memory for an emotional event stronger than a memory for a nonemotional event. How does the basolateral amygdala enhance memories formed by the hippocampus? The proposed research will use state-of-the-art neural probes to record activity of hundreds of individual neurons in the basolateral amygdala and hippocampus as rats make memories of events with either emotional or nonemotional stimuli. The study will test the hypothesis that, for emotional events, neurons in the regions will synchronize and, in doing so, modulate memory processes in the hippocampus. The research will provide insight about the brain’s natural processes of memory enhancement and will be relevant to human disorders related to emotional memory, such as post-traumatic stress disorder.
Maya Nadimpalli, PhD
ASSISTANT PROFESSOR, ROLLINS SCHOOL OF PUBLIC HEALTH, ENVIRONMENTAL HEALTH
Investigating the Burden of Antibiotic Resistance Among Atlanta Residents Through Community-Based Wastewater Surveillance
Antibiotic resistance has been declared one of the top ten global health threats facing humanity by the World Health Organization. Nearly 3 million Americans suffer from antibiotic-resistant bacterial infections each year and over 150,000 are estimated to die as a result. Due to a lack of representative data, it remains unclear whether minority populations in the United States are disproportionately burdened by antibiotic-resistant infections, although differences in risk factors (e.g., antibiotic use, occupational exposures) have been reported among racial and ethnic minorities and the socioeconomically disadvantaged. For this URC award, we propose to use community-level wastewater surveillance as a novel strategy for investigating variability in the burden of antibiotic resistance among socioeconomically diverse populations in Atlanta. We expect that pilot data generated through this award will support external funding proposals at the intersection of health disparities, antibiotic resistance, and environmental surveillance. First, we will establish laboratory methods for detecting antibiotic-resistant, priority pathogens and clinically relevant antibiotic resistance genes in wastewater. We will use these protocols to generate rigorous pilot data on the occurrence, abundance, and variability of these targets in wastewater collected from socioeconomically diverse Atlanta neighborhoods. The performance of two sampling approaches will be compared to inform an evidence-supported sampling strategy for future investigations. We will engage with stakeholders to ensure that this work leads to appropriate follow-up research and community-based action. Community-level wastewater surveillance could be a powerful and highly scalable strategy to investigate drivers of antibiotic resistance disparities in future work.
Christopher Porter, MD
ASSOCIATE PROFESSOR, SCHOOL OF MEDICINE, PEDIATRICS
Mechanisms of Aberrant Expression and Release of Siglec15 from Malignant B Cells
Outcomes for those with relapsed or refractory blood cancers like leukemia and lymphoma remain poor, necessitating the development of novel therapeutic strategies. Immune modulating therapies offer great promise for the treatment of many cancers, but a full understanding of mechanisms of immune evasion by cancer cells and failure of immune cell subsets is required to fully exploit this strategy. We have found that B cell acute lymphoblastic leukemia (B ALL) and non-Hodgkin’s lymphoma (NHL) express high levels of a newly described immuno-modulatory molecule, Siglec15 (Sig15). In addition, using mouse models of B ALL and NHL, we found that reduction of Sig15 in malignant cells promotes remission of disease in immune competent, but not immune deficient, mice with leukemia. However, little is understood about the normal regulation and function of Sig15 at the molecular level. Our additional preliminary data indicate that SIG15 expression is regulated by NFkB, is alternatively transcribed and is released from leukemia cells. With the proposed research, we will explore the hypothesis that Sig15 expression and trafficking is dysregulated in malignant B cells as compared to normal. This work will provide greater understanding of the molecular and cellular mechanisms of immune evasion mediated by Sig15, which will be critical to exploit Sig15 as a therapeutic target in the context of blood cancers.
Kara Prickett, PhD
ASSOCIATE PROFESSOR, SCHOOL OF MEDICINE, OTOLARYNGOLOGY
Ready for Surgery: A Suite of Educational Mobile Applications for Pediatric Patients
Effective preoperative education supports better patient outcomes by strengthening patients? coping skills; it may also affect long-term attitudes toward health care. Education is a core component of Enhanced Recovery After Surgery protocols and can reduce patients? anxiety, postoperative pain, and opioid consumption. Age-appropriate resources for pediatric patients are rarely available. We aim to develop a suite of interactive, child-focused mobile applications about pediatric surgery. This interdisciplinary project combines pediatric medicine with education, digital technology, and art. By designing education that can engage children in their treatment process, we aim to expand patient empowerment to younger ages.
Our team has prototyped a pilot application with procedure-specific education for tonsillectomy. The application guides patients and their families through preoperative preparation, the surgical experience, and postoperative recovery. Whereas patient education materials from major medical associations typically exceed the reading level of most Americans, our application is written at a second-grade reading level. It uses interactive features and illustrations to enhance learning. We plan to conduct a pilot trial of the tonsillectomy-focused application with patients and caregivers at Children’s Healthcare of Atlanta. The pilot will provide user feedback and a test case for the resource’s clinical benefits. We will then expand the application suite to other surgeries. The pilot application is a series of learning modules; most apply to various outpatient procedures. This structure facilitates additional versions, each of which will require only 2 units of new content. We will collaborate across surgical subspecialties and with translation services to reach a broader patient population.
Ryan H. Purcell, PhD
INSTRUCTOR, SCHOOL OF MEDICINE, CELL BIOLOGY
Convergent Mechanisms in Schizophrenia Risk Variants
Schizophrenia (SCZ) is highly heritable, but the biological mechanisms of genetic risk factors are poorly understood. Several copy number variants (CNVs) are each known to confer very high risk for SCZ and deletions at chromosome 22q11.2 (22q11.2Del) and 3q29 (3q29Del) are the highest known risk factors: approximately 25% and 40% of these individuals are expected to develop SCZ. Moreover, there is substantial overlap in the phenotypic spectra associated with these two CNV syndromes. This phenotypic convergence strongly implies some degree of convergence at underlying biological levels. Currently there has been no report of a direct comparison of biological mechanisms associated with the 22q11.2Del and 3q29Del.
We have recently developed unique, unpublished resources to specifically address the question of convergent biology in 3q29Del and 22q11.2Del. We engineered either the 3q29Del or 22q11.2Del into a neurotypical control induced pluripotent stem (iPS) cell line, thus positioning each CNV in an identical genetic background. These iPS cell lines can then be differentiated into disease-relevant cell types including neurons and cortical organoids.
Here we describe a strategy to identify meaningful points of convergence in these disorders. We will quantitatively measure the effect of each variant on the neural proteome and use unbiased pathway analysis to identify convergence and/or divergence at the level of molecular pathways and cellular compartments. These data will form the basis for future NIH proposals. In summary, this innovative study will address key questions in psychiatric genetics and generate important data that will produce novel insights into the biology of schizophrenia.
Cassandra Quave, PhD
ASSOCIATE PROFESSOR, SCHOOL OF MEDICINE, DERMATOLOGY
Targeting ESKAPE Pathogens with Egyptian Medicinal Plants
Antimicrobial resistant infections are responsible for 700,000 deaths annually, projected to reach 10 million deaths per year by 2050. Innovative approaches to identifying novel chemical compounds that could serve as the next generation of antibiotics are in high demand. Plants have played a fundamental role as the basis of the pharmacopoeia of many different cultures since ancient times. One of the oldest existing records of the medicinal applications of plants is the Egyptian “Ebers Papyrus”, which dates back to circa 1550 BC, written more than three-thousand years ago. Despite the historic importance of Egyptian flora in the foundation of medicine, many of the species documented in this record remain unstudied by the lens of modern science. Working with our collaborators in the Faculty of Pharmacy at Heliopolis University in Cairo, Egypt, Dr. Quave’s research group (including partners in the Emory Herbarium, which she curates) will undertake a research expedition to collect flora of interest in the Bahariya Oasis, a natural depression located in the Western Desert of Egypt. We will collect and authenticate herbarium specimens of each species under study and create extracts for chemical characterization and pharmacological evaluation in a panel of antibacterial and toxicity laboratory models. Undergraduate researchers will be mentored throughout the project and will contribute to the research as part of their scientific training experience.
Daniel Reines, PhD
PROFESSOR, SCHOOL OF MEDICINE, BIOCHEMISTRY
Study of a Conditional Yeast Subnuclear Granule Composed of Transcription Termination Factors
All cells organize themselves into compartments. Recent research has highlighted the importance of a certain class of proteins that can self-assemble into specialized locations within cells through a process called phase separation. In some diseases, this process goes awry and an irreversible solid that is likely toxic interferes with normal cellular function. This project will use the yeast S. cerevisiae to examine the regulated assembly and disassembly into a unique subcellular location of essential cellular proteins called Nab3 and Nrd1. These proteins are involved in the transcription of many cellular genes, but during nutrient deprivation, when cells become quiescent, they rearrange from broadly nuclear to a single puncta called the Nab3-Nrd1 granule. Commensurate with this change, the proteins bind a new set of RNAs and function in the down-regulation of the genes involved in active growth. Here we will develop as complete a catalog as possible of the set of proteins and RNAs that inhabit the granule. We will also identify genes that lie within the granule and whose transcription may give rise to it as the RNA is spooled off template DNA. This information will be developed in anticipation of a future detailed genetic and biochemical analysis of the biological and regulatory functions of this specialized place in the nucleus.