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Biological & Health Sciences

Maria Alvardo
Yerkes National Primate Research Center
Cognitive and socioemotional development after postnatal anesthesia

The pharmacology of general anesthesia is complex and still not fully understood. Although anesthetic drugs themselves are extremely safe and effective, concerns have been raised in recent years that general anesthetics may cause neurotoxicity when given early in development. In particular, animal studies demonstrate neurotoxic effects of postnatal anesthesia exposure, and epidemiological studies in children demonstrate increased risk for learning disability in children who receive anesthesia early in life. To address these concerns, neuroscientists and anesthesiologists are attempting to understand the mechanisms of pediatric anesthetic neurotoxicity. Our proposal will test a new anesthetic drug, a novel neuroactive steroid that is devoid of any GABA-mimetic activity, in a highly translational rhesus monkey model. This drug produces surgical anesthesia in neonatal rodents but is not neurotoxic and does not cause long-term behavioral impairments, but needs to be tested in rhesus monkeys, who parallel human brain development much more closely. We showed that early exposure to the common pediatric anesthetic sevoflurane impairs behavioral development in rhesus monkeys, illustrating the sensitivity of our testing procedures. By testing monkeys exposed to the new drug, we expect to find normal emotional behavior at a later developmental time point where monkeys that had been exposed to sevoflurane as infants show altered emotional reactivity. These preliminary data will provide a basis for a larger-scale study in the hopes that it may be developed into a new drug of choice for pediatric anesthesiology.

I. Raul Badell
Department of Surgery, Emory University School of Medicine
Impact of Selective CD28 Blockade on Donor-reactive T cell Programming in Transplantation

Belatacept is an immunosuppressive drug that was FDA-approved in 2011 for the prevention of graft rejection following kidney transplantation. This drug works by blocking a molecule expressed on T cells called CD28, which normally sends an activating signal to turn on T cells in the body that destroy the graft. However, this drug also inadvertently blocks another molecule expressed on T cells called CTLA-4, which normally sends an inhibitory signal to turn off T cells. We have previously shown that leaving these inhibitory signals intact results in better control of the anti-graft immune response and longer graft survival. Here, we propose to test a new strategy that specifically blocks CD28 activating signals while leaving CTLA-4 inhibitory signals intact. We will test the effect of this new, "selective" CD28 blockade on a subset of CD4+ T cells (T follicular helper cells) that are critically important in helping B cells generate antibody responses against the graft. We hypothesize that "selective" CD28 blockade will better inhibit donor-reactive T follicular helper cells and B cell responses following transplantation. Our findings will inform the development of agents aimed at targeting the CD28 pathway and help optimize immunosuppressive strategies for use in transplantation.

Misti Blount
School of Medicine: Nephrology
Ablation of excess urea reabsorption is protective against diabetic nephropathy

One of the primary functions of the kidneys is to filter and excrete waste products from our body. Each kidney is filled with tiny blood vessels called glomeruli that act as filters. Unfortunately, diabetic patients are at risk of developing kidney disease because the high level of blood sugar can damage the kidneys’ filtering system. If not managed, the kidney loses its ability to filter and will eventually fail. Once the kidney fails, the only treatment option is to have a kidney transplant or to undergo dialysis. One way diabetic patients can preserve kidney function is to maintain a low-protein diet. Although it is not completely understood why, a high-protein diet adds to how hard the kidneys have to work – ultimately damaging the glomeruli from the stress. In this project, we are investigating how one of the breakdown products of a high-protein diet, urea, can accelerate the rate of diabetic kidney disease. We speculate that if you block the kidney’s ability to reabsorb urea into the kidney tissue, the risk for developing diabetic kidney disease is lowered no matter how much dietary protein is consumed. If successful, we believe this investigation could explain the mysterious benefits of the low-protein diet for kidney function, and may lead to the creation of new drugs to slow kidney damage in diabetic patients.

Brian Dias
Psychiatry and Behavioral Sciences
Hormone-dependent sex differences in Post Traumatic Stress

Women are twice more likely than men to be affected by neuropsychiatric conditions like Post Traumatic Stress (PTS). How does one study such sex differences, and what mechanisms may underlie them? My proposal focuses on an extremely debilitating symptom of PTS – fear generalization, and examines the role of sexually dimorphic estrogen-responsive cells in such generalization. Fear generalization is a state of fear that often comes over an individual after a traumatic event resulting in fearful behavior toward stimuli not directly related to the traumatic event. Not only are the neural mechanisms underlying such generalization less studied, but so also are any sex differences in this important manifestation of PTS. Speaking of sex differences, sexual dimorphisms in brain circuits that are responsive to gonadal hormones like estrogen, progesterone, and testosterone, are among the most striking. However, there is little direct evidence that such dimorphisms contribute to sex differences in neuropsychiatric conditions. My proposal for a 2016 URC Award builds on our unpublished data demonstrating that estrogen facilitates generalization of fear after classical fear conditioning in the mouse, and asks two direct questions: (a) whether masculinizing the female brain prevents estrogen from facilitating fear generalization, and (b) whether fear generalization is mediated by a specific estrogen-responsive cell population in the hypothalamus that is present in females but not males? Data obtained from this proposal will be used in a future R01 grant application to further investigate the cellular and molecular mechanisms via which sexually dimorphic neural circuits contribute to sex differences in fear generalization.

Thota Ganesh
School of Medicine, Pharmacology
EP2 Antagonist proof of concept study in Alzheimer's animal model

I am a medicinal chemist by training but I have been collaborating with Dr. Ray Dingledine (Professor and Chair of Pharmacology) on epilepsy project for the last 5 years. Since then, I have learned design experiments, analysis and interpretation of biochemical, pharmacological and neuroscience experimental data, and I am keen to continue my career in CNS drug discovery and neuropharmacology areas. Recently, I succeeded a small grant from Alzheimer’s Drug Discovery Foundation to initiate studies on Alzheimer’s mouse model. I am also in close consultation with Dr. Allan Levey, Director of Emory's Alzheimer's Disease Research Center and Dr. Nickolas Varvel and Dr. Tom Kukar, assistant professor of pharmacology. These investigators have a significant research experience in the Alzheimer’s field and they are willing to consult on this project (see letters of support). Furthermore, I have established several other collaborations to test the efficacy of EP2 antagonist small molecules in stroke, chronic osteoarthritis pain and flu-induced inflammatory disease models at external laboratories. I believe the proposed experiments derive a preliminary, but convincing, evidence to show EP2 receptor role in the progression of Alzheimer’s pathology. If results of this project will suggest that the EP2 receptor is a drug target for AD, then the data will drive us to succeed a funding from NIH and other sources. I have recently submitted U01 application, which received an impact score of 28, but the council review is in pending. Thus, the URC funds will enable us to investigate currently ongoing experiments.

Sumin Kang
Hematology and Medical Oncology
Anti-anoikis signaling of GLUD1 in non-small cell lung carcinoma

Metastasis is responsible for most cancer deaths. Accumulating evidence suggests that cancer cells handle their metabolism different from normal cells by consuming more glucose and glutamine to generate energy and building blocks. Such unique metabolic properties make cancer metabolism an attractive target. However, up to date, little is known about how changes of metabolism in cancer cells contribute to tumor metastasis. We have recently observed that one of the major enzymes in cell metabolism called glutamate dehydrogenase 1 (GLUD1) exists more in metastatic cancer cells compared to less metastatic cancer cells from lung cancer patients. Interestingly, we found that GLUD1 turns on a signaling cascade called 'AMPK signaling' for lung cancer cells to invade and metastasize. These findings suggest GLUD1 as a novel therapeutic target for anti-metastatic therapy. We thus developed small molecule drug called R162 that can specifically “turn off” GLUD1 in lung cancer cells. In this proposal, we will first test whether and how GLUD1 governs AMPK signaling proteins in lung cancer cells to cause metastasis by comparing normal cells with cells that do not have active GLUD1. We will also test whether inhibition of GLUD1 by R162 can stop or at least slow down the invasion speed of laboratory cultured lung cancer cells as well as the metastasis of lung tumors in mouse models. In summary, this proposal will provide information about the role of GLUD1 in metastatic lung cancer, and may provide a new avenue to improve the treatment and outcome of lung cancer.

Bernardo Mainou
Identification of host and viral factors of infection of gut epithelial cells

The objective of the proposed research it to understand how the cellular environment affects viral infection and how gut cells respond to infection. Reovirus was isolated from the stool of children and although most humans are exposed to reovirus during childhood, infection seldom results in disease. Reovirus infects intestinal cells prior to spread to other organs and is shed through the stool of infected animals. The viral and cellular genes that promote infection of gut cells and how the infected host responds to infection is poorly understood. Using a bioreactor that allows studies of gut cells that more resemble what is seen in animals, we will study how the cellular microenvironment affects reovirus infection, define the host response to infection, and examine how bacteria and bacterial components that live in the gut of animals affect infection of gut cells. Together, these experiments will provide an improved understanding on how viruses infect cells in the gut, how organisms control viral infection of the intestinal tract, and the role of bacteria in promoting, or inhibiting, infection of gut cells. Knowledge obtained from experiments proposed may identify host components that could be targeted for antiviral therapy development against gut pathogens.

Gregory Melikian
Imaging of single HIV-1 uncoating in living cells

The global AIDS pandemic caused by HIV is a major cause of human mortality. While the disease progression can be controlled by current anti-retroviral therapy regimens, the quickly mutating virus develops resistance to the existing drugs. This highlights the need for discoveries of new therapeutic targets to battle infection. HIV capsid protein (CA), which forms a cone-shaped capsid shell around the virus genome, has recently emerged as a potential target for small molecule inhibitors. After the HIV capsid enters the cytoplasm as a result of virus fusion with target cells, it undergoes "uncoating", which is manifested in the loss of CA protein from the smaller viral core. Timely uncoating is important for the subsequent entry steps – reverse transcription, penetration through the nuclear pore and integration into the host genome. Studies of HIV uncoating have been impeded by the difficulties related to biochemical purification of capsids and their inherent instability. Whereas single virus imaging in living cells can circumvent these problems, the development of viable uncoating assays has been impaired by the difficulties with non-invasive labeling of HIV particles. Here we introduce a completely novel approach to HIV labeling with fluorescent proteins, which does not affect the virus’ ability to infect cells and is amenable to single virus imaging. Based on this approach, we will develop an imaging assay to follow HIV uncoating in living cells. Unique insights into HIV uncoating gained by this project will have a major impact on the field and will reveal new targets for therapeutic intervention.

Steven Presciutti
Orthopaedic Spine Surgery
The Effect of Capacitively Coupled Electrical Stimulation on Human Intervertebral Disc Cells In Vitro

Intervertebral disc degeneration (IDD) is a multi-factorial process and its underlying etiology has not yet been fully elucidated. Most of the current treatment strategies for IDD target the end-stage of the disease, simply treating symptoms while not addressing the underlying degenerative process. One of the most investigated experimental strategies to treat IDD involves the injection of different growth-promoting proteins into the disc. While such strategies have shown good initial results, delivering these proteins directly into the disc requires a local injection. This strategy has significant potential disadvantages due to its invasive nature as well as the fact that it is only a one-time dose, which is probably not enough to address a chronic condition like IDD. Clearly, there is a need to develop a longer-acting and a less invasive treatment option for IDD. A potential alternative is to use electrical stimulation. Capacitively coupled (CC) electricity is a non-invasive strategy that has previously been reported to promote bone healing and wound healing. Its effect on human intervertebral disc cells and its potential as a non-invasive treatment for IDD has not been established, however. We believe that CC is a viable treatment option for IDD but, as opposed to injections, can be applied over long lengths of time in a non-invasive manner. Therefore, we hypothesize that CC stimulation will result in either a slowing of degeneration or an actual reversal of the degenerative process in human intervertebral disc cells.

Periasamy Selvaraj
Pathology and Laboratory Medicine
Intervention of antibody-mediated arthritis with Fc receptor dimers

Rheumatoid arthritis (RA), which causes chronic joint inflammation, is one of the major debilitating autoimmune diseases among young Americans where the Fc gamma receptor expressing immune cells bind to autoantibodies deposited in joint tissues leading to tissue injury. In this proposal, we plan to investigate the therapeutic efficacy and mechanism of action of recombinant decoy Fc gamma receptor molecules in reducing inflammation in mice with arthritis. The knowledge obtained from the proposed investigation will help us understand the mechanism of autoantibody-mediated tissue damage in RA and enable the design of Fc receptor based therapeutics to treat RA in humans. Colitis and arthritis are the adverse events in cancer patients undergoing immunotherapy. These studies will accelerate the development of FcγR-based therapeutics to treat not only RA but also other antibody-mediated autoimmune diseases in humans such as colitis and lupus nephriti.

Lucas Timmins
Radiology and Imaging Sciences
Development of a Flow Circuit for the Advancement of Phase-contrast MRI in Cardiovascular Disease Diagnosis and Prognosis

Imaging represents an integral component of a clinical examination for diseases of the cardiovascular system, which account for approximately one-third of all deaths annually (>750,000) in America. Cardiac magnetic resonance imaging (MRI) is a safe, non-invasive (i.e., non-surgical), and non-ionizing radiation based (i.e., no risk of causing cancer) clinical tool that creates detailed images of the heart and major blood vessels. These images provide clinicians with accurate information on the structure and function of these organs to aid in identifying and treating patients with cardiovascular disease. Recent advancements in MRI allow for direct visualization and quantification of blood flow, termed phase contrast MRI (PCMRI), to identify dysfunction in the pumping of the heart or blockages in vessels, both of which can lead to complications associated with a reduction in blood flow to organs. To provide continued advancement in PCMRI techniques, including the development of new and more accurate imaging methods, experimental testing must be performed prior to clinical implementation. In this grant application, I propose to develop an experimental flow loop that can be used in an MRI scanner to develop, advance, and optimize PCMRI techniques. The project has two components: (i) construction of a custom-designed flow loop to reproduce the human blood flow environment and (ii) acquisition of PCMRI data in silicone replicas of major blood vessels. Successful completion of this study will provide an experimental “test-bed” for the continued advancement of PCMRI to improve the diagnosis and treatment of patients with cardiovascular disease.

Zhenqi Wang
The Role of Gabs in Normal Hematopoiesis

Hematopoietic stem cells (HSC) respond to cytokines and chemokines through activation the cell surface receptors. This leads to activation of intracellular signaling cascades. The Grb2-associated binding protein is called Gab. This family includes Gab1, Gab2 and Gab3 in mouse. They are docking/adapter proteins by connecting signaling nodes from receptors to the downstream targets. As three of them may have redundant function, their role in hematopoiesis is largely unknown. Our preliminary work showed a novel role for Gab2/3 in control of HSC cycling and survival. We have generated Gab1/2/3 compound mutant mice which are completely removed all three Gabs for the very first time. Relative to wild type mice, those mice have reduced B lymphocytes in the peripheral blood. Otherwise, they are relative healthy. In this grant, we set to test our hypothesis in Aim 1: Test whether removing Gab2/3 promotes the activation of mTORC2 independent of the phosphatidylinositol-3 kinase. In Aim 2: Test whether adapter protein Gab1 has an intrinsic role in HSC homeostasis and function. Without Gab compound mutant mice, this is impossible to assess. These studies will fill gaps in the field by exploring functional redundancy among Gab family members. Gab function in normal hematopoiesis is relevant for molecular targeted therapies for a wide range of hematologic disorders affecting humans. Obtaining this Emory URC grant is critical for my career development. It will support me to obtain key preliminary results to apply for extramural funding or NIH R01 application.