Dr. Sadia Akter is an Assistant Professor of Biomedical Sciences at Marshall University School of Medicine with over a decade of experience in bioinformatics, statistics, and machine learning. Her research focuses on integrating high-dimensional omics data, including single-cell and spatial transcriptomics, microbiome, and methylomics with AI/ML methods to uncover molecular mechanisms of complex diseases such as asthma, tuberculosis, COVID-19, addiction, and neuroinflammatory disorders. She has led bioinformatics components on multiple NIH- and NSF-funded projects and has developed machine learning frameworks for biomarker discovery and predictive modeling. As a recipient of the NIH AIM-AHEAD Fellowship and a Fellow of the American Medical Informatics Association (FAMIA), Dr. Akter is dedicated to advancing health equity through inclusive, interdisciplinary, and data-driven biomedical research.

Dr. Kristi Aldridge is an Assistant Professor in the Department of Biomedical Sciences at Marshall University Joan C. Edwards School of Medicine. She received her Bachelor of Science in Biology at Marshall University and her Doctor of Chiropractic from Palmer College of Chiropractic in Port Orange, FL. She is a licensed West Virginia chiropractor and certified acupuncturist. She has a special interest in gross anatomy and radiology education which has led her to Marshall University JCESOM to instruct anatomy, radiology and embryology.

My research interests broadly focus on understanding intestinal ion and nutrient transport processes, with emphasis on their regulation in pathophysiological states such as inflammatory bowel disease and obesity. My current work aims to decipher the functional and molecular mechanisms underlying increased intestinal bile acid absorption in obesity, with the ultimate goal of identifying potential therapeutic targets to alleviate obesity and its associated dyslipidemia which are the primary drivers of several chronic metabolic disorders such as cardiovascular disease and diabetes, the major contributors of premature mortality in this country. Using two etiologically distinct rat models of obesity—genetic and diet-induced—my lab has demonstrated that intestinal bile acid absorption, mediated by the apical sodium-dependent bile acid co-transporter (ASBT) in villus cells, is significantly elevated in obesity. Notably, high-fat diet exposure upregulated ASBT expression prior to the onset and progression of dyslipidemia, suggesting that increased intestinal bile acid absorption via ASBT may be the initiating event in obesity-related lipid abnormalities. Further investigations revealed that ASBT is upregulated not only at the cellular level, but also along the crypt-villus and caudal-oral axes of the small intestine. This multilayered upregulation of ASBT in obesity likely amplifies net bile acid absorption and contributes to enhanced fat absorption, implicating dysregulated ASBT as a central player in the pathogenesis of obesity. Ongoing research is focused on elucidating the intracellular mechanisms that regulate ASBT in proximal and distal small intestine to identify a novel, intestine-specific target to reverse ASBT-mediated bile acid hyperabsorption, thereby mitigating obesity-associated dyslipidemia and other metabolic disorders.

Research Interest 

My research interests are in the areas of cerebrovascular diseases and diabetes, specifically in developing novel predictive and therapeutic avenues for ischemic stroke, hemorrhagic stroke, and vascular complications of diabetes. My ongoing research topics include:

1. Extracellular microvesicles (MVs) and exosomes (EXs) in brain disorders and diabetic vascular complications.
2. Endothelial progenitor cells (EPCs) in neurological dysfunction, vascular protection, and tissue repair.
3. Exosomal communications between adipose tissue and brain/vessels.
4. MVs and EXs in skin injury and wound healing. 

EPC priming for functional enhancement with an angiotensin-converting enzyme (ACE2) or CXCR4 has been studied in my research. The effects of cardiovascular risk factors on the release and cargoes (proteins and microRNAs) of EPC-EXs are currently under investigation. The cross-talk mediated by MVs or EXs between endothelial cells and brain cells, as well as endothelium and keratinocytes are also currently being explored. More recently, the role of exosomes released from adipose tissue in modulating the function of vessels and the brain is being studied.

The approaches applied in my laboratory include molecular, cellular, and integrative methodologies. These methods include west blot, real-time PCR, mass spectrum, microRNA sequencing, nanosight tracking analysis (NTA), flow cytometry, etc. Animal surgery methods (MCAO, telemetric probe, osmotic minipump, microinjection) are also used in my research. The animal models used in my research include a spontaneous hemorrhagic stroke model induced in the rennin/angiotensinogen double transgenic (R+A+) hypertensive mice, collagenase-induced focal hemorrhagic stroke model, middle cerebral artery occlusion (MCAO)-induced ischemic stroke, the db/db and STZ-induced diabetic mouse models. Additionally, I use clinical samples from translational studies of diabetes and stroke patients through collaboration with clinicians.

CURRENT PROJECTS

Project 1. The role of exosomes in strokes and diabetes.

Exosomes (EXs) are small vesicles of cellular membrane released from almost all types of cells in response to physiological and pathological stimuli. EXs represent a novel way of cell-to-cell communication by transferring their molecular signatures (proteins and miRs) to target cells and tissues. Thus, extracellular EXs could be the novel therapeutic target or avenue for stroke; and could be the biomarkers for stroke and diabetes patients. These studies emphasize the protective effects of EXs derived from endothelial progenitor cells (EPC-EXs) on vascular cells and neurons. We have discovered the function of EXs from different origins by carrying different molecular signatures. We also have established the approach to identify the size, concentration, and origins of EXs by using the Nanosight Tracing Analysis system (NTA). Our recent study reported that EPC-EXs could provide therapeutic effects on ischemic stroke by alleviating the acute injury and promoting long-term neurological function recovery. We are currently investigating the mechanisms that are related to their carried proteins and miRs, such as miR-126, miR-210, etc.

The approaches used for this project include in vitro cell culture and in vivo animal models. For the in vitro model, vascular cells (endothelial cells and smooth muscle cells) and neuronal cells (neurons and astrocytes) under hypoxia/reoxygenation condition (in vitro stroke model) or oxHb stimulation (in vitro hemorrhage stroke model) will be treated with a different type of EXs. For the in vivo model, we have middle cerebral occlusion (MCAO) surgery to induce ischemic stroke, and a brain microinjection model to induce a hemorrhagic stroke. After surgery, the mice will be treated with different types of EPC-EXs. Neurological behavior will be tested before collecting the brain samples for further analysis. Moreover, we also conduct translational studies to identify the biomarker of these diseases by using NTA since we have collaborations with clinicians to collect human blood samples from stroke and diabetes patients.

Project 2. The protective role of ACE2/Ang-(1-7)/Mas in strokes and ageing by counteracting the effects of ACE/Ang II/AT1.

The renin-angiotensin system (RAS) participants in the pathogenesis of stroke, primarily through the actions of the vasoactive peptide angiotensin II (Ang II) and its pathway ACE/Ang II/AT1. Angiotensin-converting enzyme 2 (ACE2) is a homolog of ACE that is abundantly expressed in the cardiovascular-related areas of the brain and blood vessels. The primary function of ACE2 is to metabolize the deleterious Ang II into Ang-(1-7), a heptapeptide with vasoprotective actions. ACE2/Ang-(1-7)/Mas, a newly identified member of RAS, has been demonstrated to counteract the effects of ACE/Ang II/AT1. Therefore, activation of the ACE2/Ang-(1-7)/Mas pathway might represent a novel target and strategy for treating strokes. Our previous publications demonstrate that ACE2 and Ang-(1-7) protects the brain from ischemic and hemorrhagic stroke. These studies also discuss the protective effects of ACE2 on EPC function and how ACE2 improves the therapeutic efficacy in ischemic stroke. We recently found that ACE2 be carried by EPC-EXs and provide an additive beneficial effect on ageing cells by decreasing apoptosis and promoting cell viability. Further studies will verify the protective effects of ACE2 on ageing animal models. In addition, the modulation of exercise on the balance of these two pathways and its implications in strokes will be studied.

The approaches for this project include in vitro cell culture and in vivo animal models as well. For the in vitro model, ageing cells induced by Ang-II treated with EPC-EXs w/wo ACE2 overexpression. For the in vivo model, we have the Renin-transgenic hypertensive mice. We also have mice with age over six-month-old. The mice will be treated with different types of EPC-EXs.

Project 3. The role of adipose tissue released exosomes in vascular diseases.

Adipose tissue is recognized as the largest endocrine organ by releasing secretory factors to exert systemic function on the brain. Recently, emerging research showed that adipose tissue -released exosomes could be one of the mechanisms to mediate the function of the brain and vessel. exosomes of adipose origin can mediate axonal sprouting and growth, oligodendrocyte formation, tract connectivity, and remyelination. In our lab, we focus on investigating the exosomal communication between adipose tissue and the brain and vessel. It is believed that the major share of circulating exosomes is derived from adipose tissue and their cargo is directly dependent on the health of adipose tissue. Therefore, we hypothesis that the exosomes released from the different sources of adipose tissue have various functions on the brain and vessels by carrying different cargoes.

Moreover, the effect of exercise on modulating the communication of adipose tissue with the brain and vessels are also explored. It is well-known that exercise induces beneficial impacts on vascular diseases and diabetes. We have confirmed that long-term exercise could provide beneficial effects on blood pressure, body weight, and diabetic metabolic parameters. Recent studies suggest that exercise could modulate the levels of circulating exosomes and miRs, which are known to be majorly carried by EXs. We have recently demonstrated that exercise could modulate the level and contents of circulating EPC-EXs. Further studies will focus on the effects of exercise on different organs, such as adipose tissue, vessels, and the brain through the communication of EXs. The correlations of the level and contents of EXs after exercise with the outcome of strokes and diabetes will also be explored. 

LABORATORY PERSONNEL

• Shuzhen Chen, B.S. — Lab Manager
• Harshal Sawant, M.S. — PhD Student
• Smara Sigdel – Undergraduate Research Assistant 

Research Interest 

Dr. Lydia Bogomolnaya has been working in the field of microbiology for a number of years. In the past 15 years she was mainly focusing on the identification of Salmonella Typhimurium genes important for virulence in a wide range of animal models (1-3). In the course of these studies, she routinely used an extended arsenal of microbiological and molecular biology techniques, while also taking advantage of robust genetic tools available for Salmonella researchers to assign functions to previously uncharacterized genes in this bacterium. In addition, she initiated studies aimed to understand the strategies used by opportunistic pathogen Serratia marcescens to successfully colonize different surfaces (4). Recently, she became interested in understanding of physiological role of bacterial drug efflux pumps in two bacterial species, Salmonella Typhimurium and Serratia marcescens. As a faculty at Marshall University, she is currently interested in the identification of natural substrates of MacAB efflux pump in these bacteria. Identification of natural substrates of drug efflux pumps and the more complete understanding of their regulation will promote the discovery of alternative strategies to control bacterial infections.

CURRENT PROJECTS: (review how they dealt with these – tabs)

Project #1: Identification of natural functions of drug efflux pumps during infection

Non-typhoidal Salmonella enterica serotypes including Typhimurium are the leading cause of bacterial food-borne enteritis in the United States. Until recently, Salmonella isolates were highly susceptible to most of the commonly used antibiotics but in the last decade the emergence of multidrug resistant Salmonella has been reported worldwide. Serratia marcescens is an opportunistic pathogen with increasing clinical importance. S. marcescens can cause meningitis, endocarditis, infections of airway and urinary tract, especially in immune-compromised patients. Efficiency of antibiotic therapy for these patients in some cases is extremely low due to the high intrinsic antibiotic resistance of S. marcescens. One mechanism for resistance of bacteria to antibiotics is through antibiotic efflux via multidrug efflux pumps. However, little else is known about the natural functions of these pumps during infection. We found that at least one pump called MacAB present in both bacterial species protects them against reactive oxygen species (ROS). We are interested in identification of natural substrates of this pump; how these substrates protect bacteria from ROS and how substrate production is regulated.  Our studies will advance our understanding of the natural functions of bacterial efflux pumps beyond excretion of antibiotics and will aid to develop alternative strategies to control bacterial infections and augment conventional antimicrobial therapy.

Project #2: Defining the role of secreted DUF1471-containing proteins in adaptation of bacteria to different environments

  Bacteria are able to successfully exist in ever-changing environment. For a quick adaptation to a new niche, bacteria rely on secondary metabolites, peptides and secreted proteins. These molecules can participate in a number of important biological processes: signal transduction within population, production of new compounds (for example, antibiotics), formation of biofilms, and also play an important role in virulence. Gram-negative bacteria from Enterobacteriaceae family secrete in the environment a number of proteins containing DUF1471 domain with unknown function and a similar structure. The physiological role of these proteins in maintaining of bacterial viability remains unexplored. We hypothesize that bacteria utilize DUF1471-containing proteins as a network of signals to accelerate adaptation to a new environment. Our studies will be focused on identification of DUF1471-containing proteins needed for survival during infection and during antibiotic exposure.

Role of gut microbiota in health and disease

My research interests broadly encompass the role of gut microbiota cross-talk with host intestinal epithelium and its relevance to the pathophysiology of inflammatory bowel disease (IBD) and obesity.

Project 1: Probiotic bacteria stimulate intestinal nutrient/ion absorption and counteract dysregulated ion transport in IBD and infectious diarrhea

Project 2: Gut microbes regulate energy homeostasis in obesity

CURRENT PROJECTS

Project 1: Probiotic bacteria stimulate intestinal nutrient/ion absorption and counteract dysregulated ion transport in IBD and infectious diarrhea: Inhibition of electrolyte (NaCl) absorption is a hallmark of IBD and infectious diarrhea. Our studies delineated novel mechanisms underlying the beneficial effects of the probiotic Lactobacillus acidophilus in enhancing intestinal nutrient/ion absorption and counteract pathogen infection. We have partially characterized the L. acidophilus-secreted factors that stimulate intestinal Cl– absorption and counteract Citrobacter rodentium infection-induced diarrhea. My NIH-funded current research utilizes crypt-derived human intestinal organoids to delineate the molecular pathophysiology of cryptosporidiosis, a widespread diarrheal disease caused by Cryptosporidium infection and an emerging global health problem. Utilizing this novel ex vivo model as well as in vivo mouse models, our studies, for the first time, have demonstrated that Cryptosporidium infection disrupts intestinal epithelial barrier function via downregulation of key tight junction proteins and inhibits Cl– absorption by downregulating the expression of DRA (DownRegulated in Adenoma, SLC26A3), the apical membrane Cl–/HCO3- exchanger protein responsible for Cl– absorption. Our results implicate that dysregulated ion transport and impaired barrier function could be major contributing factors to cause cryptosporidiosis. Our subsequent studies will investigate the mechanisms of Cryptosporidium infection in immunocompromised hosts, such as HIV patients, in which the parasite is known to cause fatal diarrhea.

Project 2: Gut microbes regulate energy homeostasis in obesity: Obesity commonly results from imbalance in the body’s regulation of energy intake, expenditure, and storage. Gut hormones, more particularly glucagon-like peptide 1 (GLP1) and glucose-dependent insulinotropic peptide (GIP) secreted by enteroendocrine cells (EECs) of the intestinal epithelium in response to food intake regulate energy balance and glucose homeostasis by stimulating insulin secretion, regulating appetite, gut motility and gastric emptying. Generation of EECs from intestinal stem cells is controlled by the sequential expression of HATH1 and two other basic helix-loop-helix transcription factors, Neurogenin 3 (Ngn3) and NeuroD1, a process significantly decreased in obesity. This results in decreased secretion of GLP1/GIP that critically regulate appetite via gut-brain axis and blood glucose via stimulating insulin secretion. Our studies showed that the probiotic gut bacterium Lactobacillus acidophilus significantly increased EECs in the intestinal mucosa by increasing the transcription factors Math1 (mouse counterpart of Hath1) and Ngn3 in mouse intestine and mouse intestinal organoid model. Our studies unravel a novel facet of gut microbiota involvement in the pathogenesis of obesity via its effects on EEC differentiation and production of gut hormones that regulate glucose homeostasis and energy balance which will be investigated in detail.

Research Interest

I am an Instructor of Gross Anatomy at Marshall University Joan C. Edwards School of Medicine.  As an undergraduate and graduate student at Marshall University, I tailored my class schedule to feature as many courses that pertained to medicine as possible. Courses like Molecular Biology, Bacteriology, Mycology, Biomedical Physics, and Animal Physiology, on top of the required courses, started a good foundation to build on in medical school. As a student at Joan C. Edwards School of Medicine at Marshall University, I was fortunate to receive a top-class education from many of my current colleagues. My pre-clinical courses laid a strong foundation to build on and utilize in practicing medicine during my clinical years. Gross Anatomy was the course I enjoyed most. I could see and touch what we were discussing in class. For the first time, I was able to see the pathology that can result from smoking, diabetes, renal failure, abnormalities in lipid metabolism, and other diseases we were learning. Clinical rotations helped strengthen my ability to better formulate diagnoses, and come up with a plan of treatment, utilizing what I had learned in my pre-clinical years.

Additionally, clinical rotations taught me to apply all the basic science that I had gained during my first two years of medical school, in a real-world setting. While Studying for Step Two of the United States Medical Licensing Exam (USMLE), I realized I had gotten away from following physiology and the rest of my basic sciences training to formulate diagnoses, decide what medication was best, and understand and predict side effects of treatments and medications. I went to the P.A.S.S. Program to help overcome testing anxiety and prepare for USMLE Step Two. After graduating from Joan C. Edwards School of Medicine at Marshall University I started working at the P.A.S.S. Program while studying for USMLE Step Three, which is where my passion for teaching began. While at P.A.S.S., I was able to teach and tutor students from many different medical schools around the world, ranging from students studying for USMLE Step One, to physicians studying for their board examinations. I learned how to help them through testing anxiety, how to teach and refresh their basic sciences, as well as teach them how to use the basic sciences to get to the next step of diagnosis, and treatment. Teaching is very fulfilling, being able to help students become the best physicians they can be and helping them optimize learning and decrease stress are of the utmost importance. For me, medical school was a bumpy road. From health issues, uncovering a learning disability, to test anxiety, and outside stressors, I experienced more than my share of challenges while in medical school. I have grown to appreciate most of those challenges because they have helped me learn even more from medical school, than I would have learned had I sailed right through. As an instructor at Joan C. Edwards School of Medicine, I continue to learn and adapt. I plan to keep learning and employing new techniques to pass on knowledge and skills that I have learned. In the future I want to bring the use of ultrasound in to help with teaching anatomy, I look forward to broadening the topics I teach.

Research Interest

Our current research involves human induced pluripotent stem cells, CRISPR gene editing, and mouse genetics to dissect out the cell signaling function of Na+/K+-ATPase in addition to its conventional role as an ion pump. We focus on the biology of skeletal muscle cells and cardiomyocytes in physiological and pathophysiological conditions, aiming to develop new medicine and therapy to cure muscle wasting through activating the regeneration capacity of muscle stem cells.

Publications

• Huang M, Wang X, Chen Y, Pessoa M, Terrell K, Zhang J, Tian J, Xie Z, Pierre SV, Cai L (2024) Role of Na/K-ATPase α1 caveolin-binding motif in adipogenesis. Am J Physiol Cell Physiol. 27(1):C48-C64. PMID: 38708522 PMCID: PMC11371328 DOI: 10.1152/ajpcell.00168.2024
• Huang M, Wang X, Banerjee M, Mukherji ST, Kutz LC, Zhao A, Sepanski M, Fan CM, Zhu GZ, Tian J, Wang DZ, Zhu H, Xie ZJ, Pierre SV, Cai L. Regulation of Myogenesis by a Na/K-ATPase α1 Caveolin-Binding Motif. Stem Cells. 2022 Mar 16;40(2):133-148. doi: 10.1093/stmcls/sxab012. PubMed PMID: 35257186; PubMed Central PMCID: PMC8943859
• Wang X, Cai L, Xie JX, Cui X, Zhang J, Wang J, Chen Y, Larre I, Shapiro JI, Pierre SV, Wu D, Zhu GZ, Xie Z. A caveolin binding motif in Na/K-ATPase is required for stem cell differentiation and organogenesis in mammals and C.elegans. Sci Adv. 2020 May;6(22):eaaw5851. doi: 10.1126/sciadv.aaw5851. eCollection 2020 May. PubMed PMID: 32537485; PubMed Central PMCID: PMC7253156.
• Cai L, Phong BL, Fisher AL, Wang Z. Regulation of fertility, survival, and cuticle collagen function by the Caenorhabditis elegans eaf-1 and ell-1 genes. J Biol Chem. 2011 Oct 14;286(41):35915-35921. doi: 10.1074/jbc.M111.270454. Epub 2011 Aug 31. PubMed PMID: 21880729; PubMed Central PMCID: PMC3195645.
• Cai L, Das B, Brown DD. Changing a limb muscle growth program into a resorption program. Dev Biol. 2007 Apr 1;304(1):260-71. doi: 10.1016/j.ydbio.2006.12.031. Epub 2006 Dec 19. PubMed PMID: 17234173; PubMed Central PMCID: PMC1868508.
• Cai L, Cao Y, Duan E. Effects of leukaemia inhibitory factor on embryo implantation in the mouse. Cytokine. 2000 Nov;12(11):1676-82. doi: 10.1006/cyto.2000.0758. PubMed PMID: 11052819.

• Cai L, Huang C, Li Q. The adaptive thermogenesis of the gerbils’ brown adipose tissue. Dong wu xue bao. [Acta zoologica Sinica]. 1998; 44(4):391-397.

Lung cancer is the leading cause of cancer-related deaths in the USA. The death rate of lung cancer is greater than the combined death rate of breast, prostate and colon cancer.  West Virginia has one of the highest rate of lung cancers in the nation. This is due to the high rates of cigarette smoking in WV.  Nicotine is the addictive component of cigarette smoke. Studies in our laboratory try to investigate the mechanisms by which nicotine promotes the growth and progression of lung cancer.  The growth-stimulatory effects of nicotine are mediated by the alpha7-nicotinic receptor present on lung cancer cells.  We believe that our studies are clinically relevant because millions of Americans are exposed to nicotine via secondhand smoke and electronic cigarettes. Our research is also significant for lung cancer patients who use smoking cessation devices like nicotine sprays, gums and patches to quit smoking.

Our research program also explores the feasibility of nutritional interventions for the treatment of lung cancer. Capsaicin is the spicy component of chili peppers. Our published data show that capsaicin suppresses the growth of human lung cancers in cell culture and mice models. Furthermore, capsaicin also sensitizes human lung cancer cells to the pro-apoptotic effects of chemotherapeutic drugs like camptothecin.  Since, capsaicin has pungent properties, we are trying to discover second generation of capsaicin like compounds which will be non-pungent and display robust anti-cancer activity in human lung cancers

Research Interest

1. Role of beta-catenin in melanoma development and progression
2. Beta-catenin regulation of pituitary cell function

Beta-catenin is a multifunctional cell adhesion and signaling protein, important in both normal development and in some disease processes. The laboratory uses a number of cell and molecular techniques to examine the regulation of beta-catenin in melanoma. Our current hypothesis is that beta-catenin displays more gene regulatory activity because it is mis-localized.

Research Interest

Advances in technology, combined with new discoveries at the molecular level, have significantly changed the nature of biomedical research during the past two decades. New tools give investigators the opportunity to perform experiments that generate many millions of data points. Developments in our understanding of molecular mechanisms of gene expression – for example, in actions of microRNA and in epigenetic modification – have both provided new methods of experimental analysis and added to the complexity of our understanding of the molecular basis of biological function. In pursuing the understanding of complex disease, its prevention, and treatment, we typically address several different questions: Are there genetic signatures that predispose individuals to the disease? Are there environmental factors that alter gene expression in such a way as to increase an individual’s risk of disease, and if so, what is the molecular mechanism of this increased risk? Once an individual contracts a disease, what is the mechanism of progression of the disease? The ultimate aims of the research are to use answers to these interrelated questions to develop prognostic tests, interventions, and behavioral modifications to prevent, slow progression of, and treat the disease.

Due to the complexity of these questions, and of the data generated in answering them, it is no longer feasible to achieve these aims by addressing them from the perspective of a single field of research. Consequently, we need teams of collaborative researchers with expertise in their own fields and the ability to communicate and collaborate with those outside of their fields of research.
My role in this research is as a biostatistician and bioinformaticist. As a collaborative researcher, I aim to maintain a full understanding of current statistical techniques, to determine which of those techniques are best applied to problems presented by the generation of data from biomedical research, to maintain the technical skills to perform those analyses, and to present and communicate the results to the research community at large. A key aspect to this collabortive research, is the ability to communicate with researchers outside one’s own field; both in terms of understanding the research being performed in the lab, and in terms of being able to explain the choices behind the analyses being used and their results. On occasion, it may be necessary to develop novel statistical techniques in order to perform the analyses required for a particular project.

I am specifically interested in research in complex disease, including cancer and cardiovascular disease. My interest stems both from an “applied” perspective (these are diseases in which our understanding and consequently our abilities to provide treatment have the greatest potential for further progress), and from a “theoretical” perspective (the mathematical relationships between the various causes of the disease and its manifestation are intellectually appealing to me). My particular expertise is in the application of multiple hypothesis testing procedures to high-throughput genomic data. I am interested in the future to combine different sources of genomic data (such as sequence data, gene expression data, microRNA expression data, methylation data, and proteomic data) to achieve a more global understanding of the molecular mechanisms of disease. At the clinical level, this translates to pursuing a unified understanding of the interaction of “traditional” genomics with the molecular effects of environment and its effect on disease.

Research Interest

Systems approach for discovery of genetic and genomic mechanisms driving drug use and addiction-like behavior in experimental mouse populations. The overarching goal driving my research is to identify the genetic, genomic, and environmental mechanisms underlying drug addiction, a heritable disease with devastating effects on individuals and society. To this end, I use a multidisciplinary approach which includes systems genetics, cutting-edge mouse populations, and gold-standard behavioral techniques for addiction phenotyping, most notably intravenous drug self-administration.

Systems genetics using experimental mouse populations is a powerful approach that enables discovery of novel genetic and genomic mechanisms influencing disease by associating natural genotypic and phenotypic variation. The systems approach requires no a priori hypotheses about the genetic mechanisms driving a disease; the only requirement is a well-defined, construct-valid assay through which to index a disease phenotype. Using complementary methodology that includes disease phenotyping in mice, quantitative trait locus (QTL) mapping, expression QTL mapping, and gene expression to phenotype correlation, systems genetics enables identification of novel and possibly unexpected disease-associated genes. These candidates can then be validated using a CRISPR-Cas9 knockout approach. Once the effect of these genes on the disease phenotype is established, knockout mice and a range of in vivo and other neuroscience techniques can be used to uncover the mechanisms through which these genes influence the disease.

To apply a systems genetics approach, I use recombinant inbred (RI) mouse panels which are sets of isogenic strains derived from a cross of inbred founder strains. RI mouse panels are particularly suited for systems genetics studies because individual animals within an RI strain are genetically identical and, consequently, reproducible. Therefore, data from multiple experiments and laboratories can be integrated over time enabling discovery of novel genetic relationships among behavioral phenotypes, molecular phenotypes, or their combination.

Drug addiction is a critical public health issue with genetic and environmental causes for which the underlying biological mechanisms remain largely unknown. To uncover these mechanisms, I use construct-valid behavioral techniques within the context of a systems genetics approach. The intravenous drug self-administration paradigm is the gold-standard of volitional drug use assessment in rodents due to its ability to index drug taking and seeking at many stages of drug use including initiation, maintenance, and relapse. Variation in several behavioral phenotypes such as sensation seeking and incentive salience attribution are genetically associated with variation in rodent drug self-administration indicating shared biological mechanisms, but the genes and networks underlying these relationships remain elusive. Through integration of a systems genetics approach and construct-valid behavioral techniques such as intravenous drug self-administration, novel and unexpected genetic mechanisms underlying the complex psychological phenotype of drug addiction and behaviors that predict drug use and addiction can be discovered.