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Biological & Health Sciences

Francisco Alvarez
ECAS - Physiology
Contributions of microglia and peripheral monocytes to spinal cord synaptic and circuit plasticity after nerve injur

Recovery of full coordinated motor function after traumatic nerve injuries is generally poor even through peripheral nerves are capable of regeneration and reconnecting with their original muscles.  Previous work has focused on improving the speed and specificity of axon regeneration in the peripheral nerve to avoid misdirection errors or the loss of regneration capacity with time after injury.  However, using experimental models in which nerve injured induce profound reorganizations inside the spinal cord.  More specifically, the central axons and synapses of stretch-sensitive la muscle afferents are withdrawn from the spinal cord and disconnect from motoneurons and spinal interneurons causing large changes in the way the spinal cord encodes coordinated motor output.  The purpose of this investigation is to find the mechanisms responsible for the disassembly of these spinal interneurons causing large changes in the way the spinal cord encodes coordinated motor output. 

Kiwon Ban
Medicine
Generation of homogeneous population of functionally mature cardiomyocytes derived from hiPSCs via novel surface marker

Heart disease is the leading cause of death in the United States, accounting for more than 600,000 deaths per year. Due to limitedtherapeutic options for heart failure patients, cell-based therapy using cardiac muscle cells differentiated from human inducedpluripotent stem cells (hiPSC-CMs) are regarded as one of the most promising therapeutic option. However, their use in clinicalsituation is significantly limited by their immature characteristics. It has been shown that immature hPSC-CMs are 30 fold smallerthan mature hPSC-CMs, generate much weaker contractile force and also have unorganized structures. To overcome this criticalproblem, scientists have developed new techniques to generate more mature hPSC-CMs. Despite this significant progress, thequestions remain to be answered is how to specifically select those mature hPSC-CMs for further uses.Then how we can determine the maturity of hPSC-CMs and how to specifically select those mature hPSC-CMs? Unfortunately,there is no such marker that can accurately determine the maturity of hPSC-CMs yet. Therefore the goal of my study is to identifysurface protein markers that could determine maturity of hPSC-CMs. Indeed, in our preliminary study, we found a list of surfacemarker candidates whose expression is limited in the surface of mature CMs. We hypothesize that these candidates can define thematurity of hPSC-CMs and can be used to selectively isolate mature hPSC-CMs. To test this hypothesis, we will first test thosecandidate proteins for their feasibility as maturation marker. Then we will isolate mature hiPSC-CMs by using the antibodiestargeting candidate markers. Lastly, we will test and compare the therapeutic effects of  hPSC-CMs have different maturity againstthe animals in which heart failure is induced.  The results will be obtained from this study can provide new tools and resources to advance the use of hPSC-CMs for cardiacregenerative therapy, disease modeling, and drug screening and toxicity testing. First of all, these mature hiPSC-CMs will be morebeneficial for heart repair because their electric and mechanical characteristics more closely resemble those of the native heart.We believe that such mature hiPSC-CMs would provide less risk and have improved outcomes. Second, since mature hPSC- CMsmay better replicate the physiology of the adult heart, a pure population of mature hPSC-CMs will be more useful in diseasemodeling. Finally, a pure population of mature hPSC-CMs would better serve for testing efficacy and toxicity of cardiac drugs. Insummary, we anticipate that this study will be able to provide novel insight into the cardiac regenerative capacity of these maturehiPSC-CMs.

Roger Deal
ECAS - Biology
Mechanisms of transcriptional regulation by the histone variant H2A.Z

The proposed work aims to understand the operation of an essential gene regulatory mechanism that is required for proper development and has also been associated with cancer cell proliferation.  The research is highly relevant to public health in that the results of the proposed studies will provide a deeper understanding of how defects in gene regulation cause disease, and should also yield insight into how the mechanism being studied could be manipulated to control cancer cell proliferation. 

Yue Feng
School of Medicine - Pharmacology
Alternative splicing of schizophrenia-susceptibility exons in ErbB4

Schizophrenia (SZ) is a devastating cognitive brain disease affecting ~24 million peopleworldwide. The etiology of SZ is complex and poorly understood. Nonetheless, the ErbB4receptor tyrosine kinase is one of the most recognized susceptibility factors. ErbB4 is themajor receptor for Neuregulin (NRG) signaling in the brain, which plays crucial roles ingoverning normal brain development and function. The primary transcript produced by theErbB4 gene is processed into distinct mRNA molecules by alternative splicing, a naturalevent that selectively includes or excludes specific coding sequences thus greatly increasesdiversity of the proteome. These ErbB4 splice variants play distinct functions to directintracellular signaling and control different aspects of neuronal development and synapticfunction in the brain. Importantly, specific ErbB4 splice variants are aberrantly increased inthe postmortem brain of SZ patients, which is a contributing factor for SZ etiology. However,molecular mechanisms that govern ErbB4 splice variants expression in the normal brain andthe cause for dysregulation of ErbB4 in SZ are not understood. This project aims to addressthese important questions, which is a critical  prerequisite for developing novel strategies forcorrecting malfunction of ErbB4 in brain disorders including SZ.

Kareem Graham
School of Medicine - Physiology
Alternative splicing of schizophrenia-susceptibility exons in ErbB4

In multiple sclerosis (MS), immune cells called CD4+ T cells enter the brain and attack the myelin sheath that covers nerve fibers.   This eventually leads to MS clinical symptoms such as numbness and paralysis.  It is not entirely clear, however, how CD4+ T cells survive and/or function within the central nervous system (brain and spinal cord).  MS is significantly more prevalent in women than in men, but the reason for this is not known.  This lack of understanding is a tremendous barrier to developing safer and more effective therapies for MS.  We have found that a normal metabolic enzyme is “turned on” by CD4+ T cells in the brain during EAE, a well-studied mouse model of MS.  The goal of this project is to determine the role of this fat-metabolizing enzyme in the development of MS.  We will use EAE models of MS and gene-targeted (or “knockout”) mice to uncover how the enzyme influences T cell functions and myelin sheath destruction in MS.  We will uncover new functions for this enzyme in CD4+ T cell function during a mouse model of MS.  These studies will define important pathways used by myelin-attacking CD4+ T cells, which may provide clues about how or why MS develops.  Since all MS-approved drugs can improve EAE, this enzyme may be a new drug target in MS.

Yijuan Hu
Rollins School of Public Health - Biostatistics and Bioinformatics
Association Tests of Rare Variants Using Sequence Reads without Calling Genotypes

The goal of this project is to develop innovative and high-impact statistical methods foridentifying genes that influence complex human diseases. These methods will move usbeyond the current analytical paradigm that is error-prone and inefficient. Application of theproposed methods to real-world datasets should validate the methods, as well as improvingour understanding of the genetic origins of obesity and inflammatory bowel disease.Implementation of the proposed methods in user-friendly software should facilitate theapplication of the proposed methods to real NGS studies by the broad society of geneticassociation studies.

Audrey Ivanov
School of Medicine - Pharmacology
Validation of a novel C-Myc regulatory mechanism as a target for cancer therapeutic discovery

Cancer is the second most common cause of death in the US, accounting more than 500,000 deaths a year. The c-Myc protein is a well-established driver of cancer development and progression. Small chemical compounds that regulate c-Myc activity have considerable potential as novel anti-cancer therapeutics. However, direct targeting of c-Myc activity has proven to be highly challenging. We have recently identified a novel mechanism for control of c-Myc function through a novel protein-protein interaction between MKK3 and c-Myc. This previously unknown regulatory mechanism can be exploited for discovery of c-Myc targeted therapies. For this application, I will pursue the hypothesis that MKK3 is a novel regulator of c-Myc oncogenic activity, and the MKK3/c-Myc interaction represents a new target for tumors with c-Myc alterations. I propose to test the hypothesis that 1) MKK3 regulates c-Myc activity through direct binding and phosphorylation; and 2) disruption of the MKK3/c-Myc interaction reduces the tumorigenic properties of lung cancer cell lines. Successful completion of these aims will provide new insights into the mechanisms of regulation of c-Myc oncogenic activity, and will allow characterization of c-Myc/MKK3 PPI as a potential target for anti-cancer therapeutics. These results will be utilized to support a NIH R01 grant application to further characterize MKK3/c-Myc interaction as promising anti-cancer drug target in expanded study with animal models.

Jacob Kohlmeier
School of Medicine - Microbiology and Immunology
The role of IL-36 in the immune response to influenza infection 

Influenza viral infection remains a deadly disease with few pharmacological therapies, none of which modulate host response during infection. By characterizing the role of the IL-36 family of pro-inflammatory cytokines during influenza infection, we will learn more about how the immune system fights respiratory pathogens, and the impact of a novel inflammatory mediator on lung damage and disease pathogenesis.  This knowledge will inform future work towards immune-modulating therapies for influenza.

Thomas Kukar
School of Medicine - Pharmacology and Neurology
Dissecting the function of progranulin in cancer and neurodegeneration 

Progranulin (PGRN) is a secreted, multi-functional glycoprotein implicated in a number ofcostly human diseases. Excess PGRN levels are associated with diabetes and cancer, whiledecreased PGRN levels cause or increase the risk of developing Alzheimer's disease,dementia, and related forms of neurodegeneration. Multiple lines of evidence suggest thatPGRN functions by binding a receptor on the surface of cells leading to activation of specificsignals inside the cell. However, the identify of the cell surface receptor is unknown and theintracellular signals are poorly understood. In this project we will use novel techniques toanswer these key questions. This important information will provide insight into whydysregulation of PGRN levels cause disease and will help pave the way for new therapies forcancer and Alzheimer's disease and related forms of neurodegeneration.

Rita Nahta
School of Medicine - Pharmacology 
Targeting FoxM1 in triple-negative breast cancer 

Some breast cancers are called "triple-negative" (TNBC) because they do not express threekey proteins. TNBCs exhibit racial and age disparity, with an increased incidence in youngAfrican-American and Hispanic females. There are no reliable, specific therapies availablefor patients with TNBC. We must identify the factors that cause TNBCs to grow and spread.By identifying those factors, we can design new drugs to block the progression of TNBC. Wefound that a protein called  (FoxM1) is expressed at high levels in TNBCs compared to othertypes of breast cancer. Cells that are manipulated to express high levels of FoxM1 showincreased expression of proteins that cause increased movement and possibly spread of thecancer cells. Conversely, reduced FoxM1 expression changes the cancer cell so that itappears to be less aggressive. We hypothesize that targeting FoxM1 will block metastasis oftriple-negative breast cancers. We will use genetic and pharmacological approaches tomodulate FoxM1 expression in cells and tumors derived from human TNBCs and willexamine human TNBC tissues from patients to determine if FoxM1 expression is associatedwith poor clinical markers. These studies will help establish FoxM1 as a new mediator andpotential new therapeutic target in this very aggressive form of breast cancer.

John David Prologo
School of Medicine - Radiology 
Percutaneous image guided selective intra-arterial delivery of bone marrow derived mesenchymal stem cells to targeted bowel segments for the treatment of inflammatory bowel disease.  

Stem cell therapy has emerged as potentially effective in a variety of clinical settings, including musculoskeletaldegenerative diseases, cardiovascular diseases, graft versus host disease, inflammatory bowel disease (IBD), and others.Part of the challenge for researchers has been designing strategies for cells administered to patients systemically (throughan IV) to reach their site of action. For example, cells administered in the vein to treat a process in the colon must first passthrough the heart and lungs, then be distributed throughout the body through systemic arteries. Several recent studies haveshown that 1) many of these cells get “stuck” or deactivated in the lungs, and 2) direct delivery of the cells that bypassesthis process in the lungs may improve the cell’s therapeutic effects in the targeted organ.Several strategies for directly delivering the cells are being investigated, such as surgical implants for degenerative discdisease. Interventional radiologists can access very precise locations in the body (down to millimeter targets) with minimallyinvasive needle and catheter techniques. The global objective of this work is to compare these techniques of directlydelivering cells through small arteries to the bowel with the traditional intravenous dosage strategy in patients with IBD, inan analogous fashion to clinically established techniques such as the direct delivery of chemotherapy or radiation therapyto liver cancers through selected small hepatic arteries using imaging guidance.The results of these experiments will provide critical data regarding the relative number of cells that reach the bowelthrough this technique, potential changes in the molecules of the bowel following the treatments that may aid in thetreatment of IBD, as well as evaluations of the safety of using these arteries to deliver cell therapy. Once established, thisanimal model can be used to apply for larger grants to fund studies that will evaluate these techniques in the setting of IBD,and further refine the mechanisms of effect of MSCs following inta-arterial delivery. Finally, the preclinical work may betranslated to humans as an amendment to an ongoing study of intravenous MSC therapy for IBD here at Emory.

M. Katherine Rudd
School of Medicine - Human Genetics 
Epigenetic consequences of human copy number variation 

Chromosome deletions and duplications are the most common cause of intellectual disabilityand autism spectrum disorders. These chromosome rearrangements may affect theexpression of many genes; however, in most cases we do not know how dysfunction ofparticular genes leads to disease.     In this proposal, we will investigate how deletions alter the chromatin around genes nearchromosome breakpoints. We will develop a new technology, ChIP-MIP-seq, to interrogatechromatin changes due to chromosome rearrangements. We focus on genes next toterminal deletions; however, in the future we will apply ChIP-MIP-seq to other kinds ofchromosome rearrangements. This pilot study is a first step to understand how chromosomeaberrations alter genes near breakpoints and lead to neurodevelopmental disorders.

Jeff Sanders
School of Medicine - Psychiatry and Behavioral Sciences 
Oxytocin Regulation of Adolescent Fear Circuitry 

Anxiety disorders often emerge in adolescence and the majority of adults with anxietydisorders had these diagnosis in adolescence, attesting to their chronicity and frequentdevelopmental origins. Despite this morbidity, there are few effective treatment options forthese conditions. The proposed research will explore roles for oxytocin in developing fearcircuitry to innovate new ways of targeting anxiety disorders during adolescent braindevelopment.

John Steel 
School of Medicine - Microbiology and Immunology 
Overcoming sialic acid based barriers to influenza virus transmission

Influenza virus exerts a heavy annual burden of disease on human populations globallly,through epidemics and periodic pandemics. The molecular factors underpinning theepizootic emergence of human pandemic viruses are poorly understood. By combiningexpertise with a relevant animal model (the guinea pig) to test the replication andtransmission of influenza virus,  innovative molecular techniques allowing the introduction oftargeted mutations into the genome of influenza virus strains, and analytical techniquesallowing the biochemical composition of host derived mucus to be determined, we willimprove our understanding of the role of respiratory mucus in antagonizing influenzatransmission and replication, as well as better understand specific viral mutations whichsubvert the host mucus-based defenses.By elucidating the genetic and molecular determinants of influenza virus transmissionbetween human hosts, and understanding the mechanisms through which thesedeterminants function, we will enable public health measures against influenza associateddisease.

JuanJuan Wu 
School of Medicine - Gynecology and Obstetrics 
Translational regulation of endometrial VEGF production by retinoic acid

Vascular endothelial growth factor (VEGF) is a signal protein produced by cells that stimulates formation of new blood vessels (a physiological process called “angiogenesis”). It is widely accepted that VEGF is involved in angiogenesis-related (angiogenic) functions that are necessary for successful embryo implantation and development. Retinoic acid (RA) is a metabolite of vitamin A (retinol) and is known to play necessary roles in early events in pregnancy. Previously, we showed that RA works together with transcriptional activators of VEGF to rapidly induce VEGF secretion from human endometrial stromal cells through a translational mechanism of action. Our results also suggested that this effect has an oxidation-reduction (redox) sensitive component that involves increased cellular reactive oxygen species (ROS) production that acts as a "second messenger" in mediating the effects of RA on VEGF translation. The overall objective of this proposal is to elucidate the precise molecular mechanisms played by RA in regulating VEGF protein translation in the endometrium. Experiments proposed in this proposal are designed to study the action of RA on three well-established redox sensitive mechanisms that can regulate translational of VEGF: internal ribosomal entry site (IRES)-mediated VEGF translation, eukaryotic translation initiation factor 4E (eIF4E)-mediated cap-dependent translation and endoplasmic reticulum stress-mediated VEGF translation. These experiments will allow for an expanded evaluation of the roles of RA in reproductive biology. Results obtained from this proposal may be exploited for designing new drugs which target the retinoid pathway for increasing the angiogenic function of endometrial stromal cells of woman with infertility or early miscarriage, thereby potentially altering the course of their reproductive failures.