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Biological & Health Sciences

George R. Beck, Jr., PhD
SOM: Endocrinology
Immune modulation by dietary phosphorus and the regulation of bone metabolism

A significant factor that contributes to age related bone loss is the high dietary intake of inorganic phosphate (Pi), characteristic of the US population. We have recently reported that high dietary Pi intake in mice results in profound bone loss. Further, we have correlated changes in bone serum markers between mice on high Pi diets and human volunteers consuming increased Pi diets. These studies also identified osteopontin (OPN) as a Pi responsive circulating factor in both mice and humans. OPN is a pleotropic pro-inflammatory cytokine that can both activate T cells as well as acts as a secreted effector protein and is required for osteoclastic bone resorption. The overall goal of the proposal is to investigate the role of T cells in dietary Pi induced bone loss with a focus circulating OPN. This proposal will test the hypothesis that T cells contribute to the bone loss of high dietary Pi consumption through the actions of OPN. To address these questions we will use state-of-the-art transgenic mouse models in combination with a highly innovative approach of adoptive T cell transfer from these transgenic mice. This approach will allow us to determine the role of nutrition in the upstream regulation of specific T cell populations, inflammatory cytokine production, and the downstream effects on bone biology. This application has the potential to provide critical new information about the mechanism(s) by which nutrition and the immune system contribute to bone loss.

Guangping Chen, PhD
SOM: Physiology
UT-B urea transporter: Novel negative regulator of bladder tumorigenesis

Bladder cancer is one of the most common cancers. Despite significant progress in the cancer research field overall, little has been achieved in bladder cancer in the same time and the molecular mechanism of bladder tumorigenesis and cancer progression remains poorly understood. We have new findings that the SLC14A1 gene, which encodes urea transporter UT-B and mediates urea transport across the cell membrane, was significantly suppressed or aberrantly expressed in bladder cancer. We, for the first time, identified a tumor specific UT-B124 with a 24-nt in-frame deletion in exon 4 from bladder cancer patients and the 24-nt deletion causes a functional defect. High urea exposure can affect cells in many ways. Given that the bladder is the only organ that is constantly in contact with a high concentration of urea, bladder UT-B may play a critical role in preventing bladder tumorigenesis. We propose that dysfunction of UT-B results in intracellular urea accumulation and subsequently activate a carcinogenic pathway and/or render the bladder cells susceptibility to carcinogen exposure. In this one-year proposal, we plan to determine (1) the underlying mechanism of the impaired function of the tumor-associated UT-B24 mutant; and (2) whether dysfunction of UT-B dismantles the bladder cells protection against urea/carcinogens and whether restoration of UT-B expression in bladder cancer cells reverses or reduces bladder cell malignancy.

Graeme L. Conn, PhD
SOM: Biochemistry
Regulation of the innate immune protein oligoadenylate synthetase 1 (OAS1)

Precise control of protein synthesis is essential for maintenance of normal cellular function and is central to innate antiviral responses within the cell. For example, the innate immune system protein 2-iquest;-5-iquest;-oligoadenylate synthetase (OAS) detects cytosolic double-stranded (ds)RNA to initiate a translational control response, via activation of the latent ribonuclease L (RNase L), which limits viral protein synthesis and thus replication. Structures of OAS1 and OAS1-dsRNA complexes have revealed important insights into OAS1 activation: dsRNA binding drives a functionally essential reorganization of the OAS1 active site. However, my group's recent discovery of a novel single-stranded RNA motif which strongly potentiates activation of OAS1, and new unpublished data presented here, strongly argue that we still have an incomplete understanding of how specific RNA features and their contexts combine to drive potent activation of OAS1. The goal of this proposal is to position my lab to address this critical gap. Our new data show that the model dsRNA used for OAS1 structural studies contains competing activating and non-activating OAS1 binding sites, and that currently ill-defined molecular mechanisms direct binding orientation in solution and thus control the potency of OAS1 activation. Further, we have found that ATP binding induces distant changes in the RNA binding surface of OAS1, supporting our novel hypothesis that catalytically productive RNA binding is dependent on an unappreciated level of allosteric regulation by ATP. This proposal describes a focused research plan to test our hypotheses and to thereby define fundamental mechanisms of OAS1 regulation by dsRNA and ATP.

Jaime Hatcher-Martin, MD, PhD
SOM: Neurology
Safety and Efficacy of propranolol in the treatment of tardive dyskinesia

Tardive dyskinesia (TD) is a disabling, embarrassing, and often irreversible, movement disorder caused by medications, such as antipsychotic and antinausea medications, that block the effects of a brain chemical, dopamine. Severe cases can be associated with difficulty speaking, chewing, and swallowing, and tongue mutilation. TD also results in writhing movements of the limbs, trunk movements such as rhythmic rocking or thrusting motions, and repeated contractions of the diaphragm which can be life threatening. While the frequency of TD was expected to decrease because of a lower incidence with newer antipsychotics, more widespread use of these and other offending agents still contribute to a substantial increase in the number of cases annually. Despite significant disability and prevalence, there are no specific medications approved for the treatment for TD and inappropriate management is common. Propranolol, an FDA-approved beta-blocker since 1967, was studied 30 years ago, mostly via small studies or case descriptions with limited controls. Despite initial positive results, a large, long-term appropriately-controlled trial was never performed. Several direct observations in our clinic have shown substantial beneficial effects of propranolol in TD. The goal of this study is to evaluate the effectiveness of propranolol for the treatment of TD in an appropriately designed trial. This could provide the level of evidence needed to pursue a larger scale multicenter trial through the NIH NeuroNEXT program of which Emory is a site, and Dr. Stewart Factor is a primary investigator. NeuroNEXT infrastrucure helps facilitate rapid development and implementation of studies in neurological disorders.

Deanna Kulpa, PhD
SOM: Pediatrics
Determining the contribution of CD4+ T cell subset phenotype on HIV latency and reversal in an in vitro latency model

The latent HIV-1 reservoir persists in individuals on ART predominantly in a heterogeneous pool of CD4+ T cell subsets endowed with distinct functional and survival capacities. HIV-1 persists in individuals on ART in infected stem cell (TSCM), central (TCM) transitional (TTM) and effector (TEM) memory cells. More recently, effector CD4+ T cell subsets such as T Helper 17 (Th17), regulatory T cells (Treg) and follicular T helper cells (Tfh) have also been shown to contribute to HIV persistence in vivo. However, the mechanisms responsible for the persistence of the HIV reservoir in these distinct CD4+ T cell subsets in vivo are still largely unknown, which has hindered the design of effective eradication strategies. One eradication strategy, the ¿shock and kill¿ approach, aims to eliminate the HIV reservoir through latency reversal and immunological clearance in all latently infected CD4+ T cells. In order to efficiently reverse latency across cell populations with diverse activation states and availability of transcription factors, this strategy will need to address the inherent molecular differences that define the different memory and effector CD4+ T cell subsets. To facilitate the study of compounds that may effectively eradicate HIV from all infected CD4+ T cell subsets, I developed LARA (Latency and Reversion Assay), a primary cell based in vitro model that supports the study of the mechanisms that trigger the establishment of HIV latency as well as those that lead to maintenance and latency reversion in TSCM, TCM, TTM, Th17, Treg, Tfh subsets in a single assay. My preliminary studies specifically focused on the memory CD4+ T cell subsets TCM, TTM, and TEM and their responsiveness to different classes of latency reversing agents (LRAs). The studies with LRAs revealed responses specific to each memory subset, including compounds that significantly reversed latency in all subsets but with a range of efficiency (bryostatin) to those that demonstrated subset specificity (IL-15). Significantly, I demonstrated that TEM cells displayed a more activated profile compared to TCM, which translated to enhanced efficiency in responsiveness to multiple LRAs and allowed the identification of mechanisms associated with the compounds that reactivate latent HIV in all subsets. Understanding the responsiveness of CD4+ T cell subsets to LRAs will accelerate the development of anti-latency therapies that will interfere with HIV persistence in vivo. My central hypothesis is that latency reversal efficiency in the different effector and memory CD4+ T cell subsets will be reflective of the relative activation status of these subsets, which can be overcome by directed differentiation to a more activated phenotype. In Aim 1, I will use a multi-compound approach to identify therapeutic strategies to disrupt HIV latency in distinct memory and effector CD4+ T cell subsets, and examine the role of subset phenotype on latency reversal efficiencies. In Aim 2, I will determine if CD4+ T cell differentiation to an activated subset phenotype will further enhance latency reversal efficiency in the most long-lived memory CD4+ T cell subsets such as TSCM and TCM. These data will aid in the identification of pathways that may be critical in specific CD4+ T cell subsets for HIV latency, and together, these data will help define combinations of LRAs that can reactivate latent HIV across diverse CD4+ T cell subsets, a critical prerequisite for the success of HIV eradication strategies.

Benjamin Lopman, PhD
SPH: Epidemiology
Changing etiology of acute gastroenteritis in Indian children in the rotavirus vaccine era: the role of Sapovirus and Astrovirus

Diarrheal diseases are a major cause of childhood mortality and morbidity in Indian settings, and viruses are the main causative agent. However, aside from rotavirus, little is known on the etiologic role of viral causes. We will test a large collection of samples and use data from a cohort of children born in a semi-urban slum and followed for diarrheal disease for three years as well as samples from children hospitalized with diarrhea to understand the burden of disease due to enteric viruses other than rotavirus, specifically astroviruses and sapoviruses. Rotavirus vaccines are currently being rolled out in India and this intervention is sure to shift the ecology and epidemiology of diarrheal diseases in that setting. Accordingly, we will use these analyses to gain understanding of the changing dynamics of these enteric viruses following introduction rotavirus vaccine into the national immunization schedule. Strategically, this project will solidify the relationship between the Wellcome Trust Research Laboratory at the Christian Medical College, Vellore and the Emory University Rollins School of Public Health by establishing a new collaboration between RSPH PI Lopman and CMC PI Praharaj. This collaboration furthers Emory’s strategic goal to increase our visibility through collaborations with global centers of academic excellence. Moreover, this project addresses a problem of major health concern in India, a priority setting, and will produce the foundations for further collaborations and grant applications.

Cassandra Quave, PhD
SOM: Dermatology
Investigation into the antibacterial potential of medicinal plants of the Aegadian Islands, Italy

Multidrug-resistant (MDR) bacterial pathogens present an alarming challenge to healthcare providers. An estimated 700,000 people die annually due to antimicrobial resistant (AMR) infections, and this number is expected to reach 10 million by the year 2050; new solutions are urgently needed. Compounding this problem, there is a lack of novel chemical scaffolds in the pipeline for antibiotic development; the last new registered class of antibiotic was discovered in 1984. Plants are a potentially rich source of novel chemical entities for future drug development. Many of our top pharmaceuticals originated from plant natural products, including drugs for pain management, cancer therapeutics, anti-infectives, and more. However, with an approximately 450,000 flowering species on Earth, it is not feasible to examine all plant life for new compounds. Instead a more targeted approach can prove useful. The study of human interactions with plants for the purpose of medicine can reveal unique sources of potentially novel bioactive compounds. Known as the ethnobotanical approach to drug discovery, this process integrates tools from multiple disciplines (e.g., anthropology, botany, chemistry, microbiology) in the search for new drugs from nature. Here, we will leverage this approach to examine the medicinal plants from the Aegadian Islands in Sicily for their potential antibacterial activity against top priority antibiotic resistant pathogens. This will be achieved through three core activities in the project: 1) ethnobotanical field work and collection of plant specimens; 2) chemical extraction of plant materials and antibacterial testing against antibiotic resistant bacteria; and 3) development of opportunities for research engagement and training in the plant sciences.

Srikant Rangaraju, MD
SOM: Neurology
Biophysical and immunological characterization of human Kv1.3 channel polymorphisms

Peripheral immune cells called effector-memory T cells are key drivers of autoimmune disorders such as psoriasis, multiple sclerosis and rheumatoid arthritis. In neurodegenerative disorders such as Alzheimers disease, brain immune cells called activated microglia mediate inflammation that hastens disease progression. The potassium channel Kv1.3 is highly expressed and is a master regulator of immune functions of effector-memory T cells as well as activated microglia. Based on existing literature and our previous work strongly supporting the pathologic importance of Kv1.3 channels in human disease, we suspect that genetic polymorphisms (or variants) in the Kv1.3 gene may affect channel function, immune function and therefore alter the risk and severity of immune-mediated diseases. Over 200 Kv1.3 variants have been identified in humans but we do not know whether these variants have any biological significance. Of 218 Kv1.3 variants, we have identified 10 that are predicted to biophysically alter how the Kv1.3 channel opens in response to changes in membrane voltage. In this pilot proposal, we will study the biophysical effects of these 10 human Kv1.3 genetic polymorphisms using patch clamp methods. We will then determine whether these polymorphisms alter migration, inflammation and cytokine production by immune cells and whether they Kv1.3-expressing immune cells to escape blockade by highly potent Kv1.3 channel blockers. The pilot proposal will provide critical data that may pave the way for future in-vivo and human genetic studies to determine the association of Kv1.3 variants with human autoimmune and neurologic diseases.

Owen B. Samuels, MD
SOM: Neurosurgery
Low chloride containing hypertonic solution for osmotherapy in acute subarachnoid hemorrhage patients

Subarachnoid hemorrhage (SAH, is a form of life threatening stroke usually due to leaking of blood into the brain from an aneurysm. One in five patients will die in the first month and many become disabled and with severe neurologic disability. Among the most severe complications of SAH is brain edema, which causes a massive increase in the pressure within the skull. The result is further injury to the brain, which can be life threatening. Study question and hypothesis: Hyperosmolar therapy is one of the mainstay treatments for SAH-related cerebral edema and cerebral arterial vasospasm, to reduce delayed cerebral ischemia, improve outcome, and reduce mortality. Currently, hypertonic saline is a commonly administer solution used for hyperosmolar therapy. An alternative solution, Na-Chloride/Na-Acetate, is used in cases in which hyperchloremic metabolic acidosis is noted. Recent evidence from the literature has established an association between high intravenous (IV) chloride load with worsened outcome in medical and surgical critically-ill patients. Of note, hypertonic saline, contains a super-physiologic chloride load. We hypothesize that by using the alternative “chloride lean” solution, the AKI rates will be reduced, and clinical outcomes will improve. Study design: The study is designed to be a double-blind prospective pilot clinical trial. Patients admitted to the NeuroICU for an aneurysmal SAH will be eligible for this study. Eligible patients will be randomized to receive either the standard sodium-chloride solution, or the alternative, sodium-chloride/sodium-acetate. In addition to the standard of care management of patients with SAH, blood, urine, and cerebrospinal fluid samples will be stored for future analysis. The primary outcome will be a reduction in the rate of acute kidney injury. Potential impact: This research potentially could improve future management of critically ill subarachnoid hemorrhage patients, and perhaps other patient populations that need osmotherapy for severe brain swelling.

Yanhua Wang, MD, PhD
SOM: Nephrology
Role of aA2:L31 vasoactive hormone, adrenomedullin, in mediating urine concentrating ability

Water reabsorption is crucial to the production of concentrated urine in the renal medulla. The ability to concentrate urine is absolutely necessary for maintenance of water homeostasis. However, to maintain water homeostasis when challenged, the kidney needs to be able to regulate water excretion to alter urine osmolality independently of vasopression (AVP). I tested the role of a novel vasoactive hormone, adrenomedullin (ADM), on water transport. My preliminary tubule perfusion data show that ADM increases osmotic water permeability. mRNA of ADM and its receptor components, CRLR and RAMP 2&3, is expressed in inner medullary collecting ducts (IMCDs). These data indicate that ADM may synergize with AVP for maximal stimulation of AQP2 activity. My hypothesis is that ADM stimulates water transport in the inner medulla through a cAMP-pathway to limit the loss of water and solute. The specific aim I proposed is to determine the regulation of water transport by ADM in the inner medulla. I will determine if ADM and its receptor components (CRLR, RAMP2 and RAMP3) are expressed in the IM at both mRNA and protein levels, and whether ADM increases osmotic water permeability by activating cAMP-mediated AQP2 phosphorylation and membrane accumulation. The regulation of AQP2 by ADM will advance our understanding of how water permeability support the urine concentrating mechanism. I believe that my proposed studies are highly significant as they are likely to yield new information on mechanisms underlying the dysregulation of water homeostasis that occur in common clinical disorders, such as congestive heart failure, cirrhosis, and nephrotic syndrome.

David Yu, MD, PhD
SOM: Radiation Oncology
ole of CHD5 in the Replication Stress Response

The replication stress response (RSR) is a signaling network that recognizes challenges to DNA replication and coordinates diverse DNA repair and cell cycle checkpoint signaling pathways. The RSR is critical both for the prevention of carcinogenesis by acting as a barrier against genomic instability and for determining the response of cancer to treatments that induce DNA damage and replication blocks. The RSR promotes activities necessary to maintain genome integrity following replication stress including arresting the cell cycle, stabilizing the stalled replication fork, and facilitating replication recovery; however, the mechanisms mediating these activities and how their dysregulation leads to a tumor permissive phenotype and tumor cell treatment resistance are poorly understood. We recently identified chromodomain helicase DNA binding protein 5 (CHD5) as a novel regulator of the RSR. CHD5 is a member of the CHD family of chromatin remodeling enzymes and functions as a tumor suppressor in a number of malignancies. In this regard, our preliminary results show that CHD5 deficiency results in spontaneous accumulation of DNA damage, sensitivity to replication stress, impairment in recovery from replication arrest, and a defect in ATR-dependent phosphorylation of CHK1. Moreover, we found that low CHD5 expression is prognostic for poor outcome in patients with pancreatic cancer. These findings imply a critical role for CHD5 in the RSR that may provide an underlying mechanism by which CHD5 deficiency results in tumorigenesis and CHD5 expression determines clinical outcome; however, the precise functions of CHD5 in the RSR are not clear. We hypothesize that CHD5 maintains genome integrity, at least in part, by directing an ATR-mediated RSR through chromatin remodeling. To test this hypothesis, we propose to 1) Dissect how CHD5 functions in DNA replication and the DNA damage response (DDR), 2) Determine the role of CHD5 in regulating ATR function in the RSR. Completion of these aims will provide new insights into how CHD5 maintains genome integrity and prevents cancer. Moreover, given the critical role of the RSR in determining the response of cancer to treatments that induce DNA damage and replication blocks, this work also has significant therapeutic implications for using CHD5 as a novel target or biomarker for cancer treatment. We anticipate that completion of this work will provide preliminary data necessary for a competitive R01 proposal based on defining the role of CHD5 in directing the RSR.