Joseph G. Verbalis - US grants

Hypoosmolality and hyponatremia caused by the syndrome of inappropriate antidiuresis (SIAD) is a significant cause of morbidity and mortality in hospitalized patients. However, despite recognition of this clinical disorder for almost 30 years, many aspects of the pathogenesis of hypoosmolality with inappropriate antidiuresis remain unclear. In part this is due to the lack of a good animal model allowing sustained hypoosmolality without escape from antidiuresis. This proposal describes the development of such a model using continuous infusions of vasopressin or 1-deamino-(8-D-arginine) vasopressin in rats eating a balanced liquid diet of sufficient caloric density to maintain stable body weights. The experiments proposed will utilize this animal model to characterize the pathogenesis of hypoosmolality with inappropriate antidiuresis and to study the physiological adaptations which occur in response to states of chronic severe hypoosmolality, specifically: 1) the mechanisms of cellular adaptation to sustained extracellular hypoosmolality, 2) the patterns of neurohypophyseal secretion of vasopressin and oxytocin after adaptation to sustained extracellular hypoosmolality, and 3) the mechanisms of brain adaptation to sustained extracellular hypoosmolality and the consequences of such compensatory changes for brain hydration following subsequent correction to normotonicty. A better understanding of the pathophysiology during sustained hypoosmolality in the rat should also be of direct relevance to several related aspects of human SIAD, specifically: 1) the relative importance of cellular inactivation of solute versuys cellular loss of solute in the pathogenesis of hyponatremia, 2) the mechanisms responsible for the reset osmostat pattern of vasopressin secretion in SIAD, and 3) the potential relation between hypoosmolality and demyelinating disorders such as pontine and extrapontine myelinolysis as well as the pathophysiological mechanisms leading to such demyelinative changes. Applying existing methods and procedures in this laboratory to an established animals model of sustained severe hypoosmolality will allow completion of studies which should therefore lead to significant advances in our understanding of how organisms, including humans, adapt to derangements in extracellular osmolality. Such knowledge should in turn permit a more enlightened approach to the clinical management of disorders of water and elecrolyte metabolism.

Salt appetite is a complex behavior that occurs under a variety of conditions, many of which are appropriate responses to real or perceived deficits of body sodium but some of which are not. As with other behaviors, interactions between peripheral and brain mechanisms are responsible for the presence, or absence, of salt appetite. In the brain it is now apparent that both excitatory and inhibitory components influence the expression of salt appetite. Studies from many laboratories have implicated several neuropeptides and several areas of the brain as potentially being involved in the control of salt appetite, but to date there is no consensus about the brain pathways essential for either excitation or inhibition of this behavior. Recent studies from our laboratories have shown that neuronal expression of the immediate early gene product Fos can identify neural pathways that are activated by a specific stimulus, and can differentiate these from pathways activated by related but nonetheless distinct stimuli. This methodology therefore enables an assessment of the brain circuits that are activated by stimuli that excite or inhibit specific behaviors under defined experimental conditions. The studies in this project utilize fos expression as a marker of neuronal activation after treatments known to excite or inhibit salt appetite in rats. Analysis of the stimulated patterns of Fos activation in response to multiple different treatments will allow identification of a common subset of brain areas that are activated in response to excitation or inhibition of salt appetite. Additional studies will pair excitatory and inhibitory treatments to ascertain the patterns of brain Fos activation under conditions of mixed stimuli that likely occur under physiological circumstances, and will compare the patterns of brain Fos activation in response to treatments that inhibit salt appetite to those accompanying physiological satiation of this appetite. Analysis of the neurochemical phenotypes and connectivity of the neurons activated to express Fos in response to treatments that either excite or inhibit salt appetite will allow analysis of the brain pathways involved in its control. These studies will therefore produce detailed descriptions of the brain areas that are essential for both excitation and inhibition of salt appetite in the rat, thereby defining the functional neuroanatomical basis of this important homeostatic behavior.

Hyponatremia is the most common electrolyte disorder of hospitalized patients in the United States and is a significant cause of morbidity and mortality. Clinical studies have provided important insights into this disorder, but many question remained unanswered about virtually every aspect of hyponatremia. Because controlled clinical trials are difficult and potentially dangerous in this population, studies using an animal model that mimics the clinical features of hyponatremia in human patients offers the best opportunity to better understand the pathophysiology of this disorder. During the first period of funding of this grant such an animal model was developed and is widely utilized for studies of experimental hyponatremia. During the second period of funding we employed this model to study how the brain adapts to hyponatremia, and the mechanisms that allow "de-adaptation" once the hyponatremia is corrected to normonatremic levels. Although we now understand much more about the process of brain adaptation to and de-adaptation from hypoosmolar conditions, other tissues, particularly the kidney, must adapt to induced hypoosmolality as well. Perhaps the most important and unique way in which the kidney adapts is via renal escape from anti-diuresis. In both animal models of sustained AVP administration and patients with SIADH, water loading results in initial water retention and progressive hyponatremia which is then followed by escape from the induced anti-diuresis, which is characterized by increased free water excretion despite sustained administration of AVP, allowing water balance to be res-established and the serum [Na+] to be stabilized at a steady, albeit decreased, level. Although this phenomenon has been described since the earliest studies of AVP-induced anti-diuresis, there is at present no consensus regarding the cellular mechanisms underlying this important homeostatic response. In preliminary studies we have found a marked down-regulation of kidney aquaporin-2 protein and mRNA levels which correlate temporarily with the onset of renal escape from DDAVP-induced anti-diuresis. The present application proposes to study the extracellular, membrane, and intracellular mechanisms mediating this response. Specifically, we will: 1) characterize the changes in cortical and medullary kidney aquaporin-2 mRNA and protein expression during renal escape from anti-diuresis and following water restriction, 2) ascertain whether extracellular signals are involved with triggering the down-regulation of aquaporin-2 expression during renal escape from anti-diuresis, 3) determine whether changes in AVP receptor expression or binding correlate with changes in aquaporin-2 expression in inner medullary tissue during renal escape from anti- diuresis, and 4) study the cellular mechanisms associated with renal escape from anti-diuresis, and specifically whether decreased activity of the adenylate cyclase-cAMP cascade in the medulla accompanies the down- regulation of aquaporin-2 expression during this time. These studies should lead to an elucidation of the cellular mechanisms underlying one of the most basic and intriguing unanswered question about clinically hyponatremic disorders.

DESCRIPTION: (Adapted from the Investigator's Abstract) Recent data have shown that central oxytocin pathways constitute an important component of the inhibitory controls of ingestion of both food and salt (NaCl) in rats. Since central oxytocin-mediated inhibition of ingestion appears to be generalized to many different solutes, we postulate that similar central control mechanisms may also influence the ingestion of ethanol. The studies proposed in this application will directly address this hypothesis by assessing the effects of reversible antagonism of oxytocin receptors and irreversible destruction of central oxytocin-receptor bearing cells on the consumption of ethanol by laboratory rats. Preliminary studies utilizing central administration of the toxic A chain of the plant cytotoxin ricin conjugated to oxytocin have indicated that this treatment leads to a robust consumption of ethanol in rats, which then continues and leads to the development of tolerance to acutely administered ethanol. Analogous effects were reproduced by central administration of the reversible oxytocin-receptor antagonist L366,946, confirming that these are specific oxytocin effects. To fully understand the participation of central oxytocin pathways on ethanol ingestion it will first be necessary to assess the effects of ethanol to modulate central oxytocin pathways that inhibit the consumption of ordinary ingesta, such as food and NaCl solutions. Initial studies will be done to evaluate the effect of acute ethanol administration on basal, inhibited, and stimulated ingestive behavior in rats, and will correlate these effects with measured changes in central and peripheral oxytocin release. Additional studies will extend these observations to a direct assessment of the effect of exogenous administration of oxytocin on ethanol-induced modulation of ingestive behavior. These experiments will provide the basis for a comprehensive characterization of the neural mechanisms responsible for oxytocin antagonist and ricin-oxytocin potentiation of ethanol consumption in rats. The models we characterize will then be employed to study potential developmental and gender- related variables that influence ethanol consumption. The combined studies in this proposal will therefore address several important unanswered questions about central mechanisms that influence the initiation and continued consumption of alcohol in laboratory animals. They will also likely have important implications for future studies of the brain pathophysiology and adaptive neuronal mechanisms that accompany the behavioral and functional consequences of chronic alcohol abuse, which cannot be as easily evaluated in human subjects.

Hyponatremia is the most common electrolyte disorder of hospitalized patients in the United States and is a significant cause of morbidity and mortality. Clinical studies have provided important insights into this disorder, but many question remained unanswered about virtually every aspect of hyponatremia. Because controlled clinical trials are difficult and potentially dangerous in this population, studies using an animal model that mimics the clinical features of hyponatremia in human patients offers the best opportunity to better understand the pathophysiology of this disorder. During the first period of funding of this grant such an animal model was developed and is widely utilized for studies of experimental hyponatremia. During the second period of funding we employed this model to study how the brain adapts to hyponatremia, and the mechanisms that allow "de-adaptation" once the hyponatremia is corrected to normonatremic levels. Although we now understand much more about the process of brain adaptation to and de-adaptation from hypoosmolar conditions, other tissues, particularly the kidney, must adapt to induced hypoosmolality as well. Perhaps the most important and unique way in which the kidney adapts is via renal escape from anti-diuresis. In both animal models of sustained AVP administration and patients with SIADH, water loading results in initial water retention and progressive hyponatremia which is then followed by escape from the induced anti-diuresis, which is characterized by increased free water excretion despite sustained administration of AVP, allowing water balance to be res-established and the serum [Na+] to be stabilized at a steady, albeit decreased, level. Although this phenomenon has been described since the earliest studies of AVP-induced anti-diuresis, there is at present no consensus regarding the cellular mechanisms underlying this important homeostatic response. In preliminary studies we have found a marked down-regulation of kidney aquaporin-2 protein and mRNA levels which correlate temporarily with the onset of renal escape from DDAVP-induced anti-diuresis. The present application proposes to study the extracellular, membrane, and intracellular mechanisms mediating this response. Specifically, we will: 1) characterize the changes in cortical and medullary kidney aquaporin-2 mRNA and protein expression during renal escape from anti-diuresis and following water restriction, 2) ascertain whether extracellular signals are involved with triggering the down-regulation of aquaporin-2 expression during renal escape from anti-diuresis, 3) determine whether changes in AVP receptor expression or binding correlate with changes in aquaporin-2 expression in inner medullary tissue during renal escape from anti- diuresis, and 4) study the cellular mechanisms associated with renal escape from anti-diuresis, and specifically whether decreased activity of the adenylate cyclase-cAMP cascade in the medulla accompanies the down- regulation of aquaporin-2 expression during this time. These studies should lead to an elucidation of the cellular mechanisms underlying one of the most basic and intriguing unanswered question about clinically hyponatremic disorders.

human therapy evaluation; arginine vasopressin; hormone inhibitor; hyponatremia; drug screening /evaluation; diuretics; oral administration; patient oriented research; clinical research; blood chemistry; human subject;

arginine vasopressin; drug screening /evaluation

[unreadable] DESCRIPTION (provided by applicant): Georgetown University Medical Center, MedStar Health, MedStar Research Institute and Virginia Tech are submitting a planning grant to prepare an application for a Clinical and Translational Science Award. This application outlines the planning process for the establishment of a Center for Clinical and Translational Science and a Department of Translational Science at Georgetown University that will capitalize on the strengths of our respective institutions. We describe the creation of a broadly-based, diverse network for the performance of high quality clinical/translational research that is thoroughly integrated with an innovative curriculum for training clinical investigators at multiple different professional levels. Over the course of the planning year, we propose to pursue the following specific aims in order to reach these goals: [unreadable] 1. Establish a Center for Clinical and Translational Science and Department of Translational Science at Georgetown University, MedStar Research Institute/MedStar Health and Virginia Tech. [unreadable] 2. Create advanced degree-granting programs in clinical and translational science at Georgetown University, MedStar Research Institute/MedStar Health and Virginia Tech. [unreadable] 3. Plan roadmap training grants (K12, T32) to complement the educational mission of the Center. [unreadable] 4. Enhance the infrastructure for clinical investigation at Georgetown University and MedStar Health. [unreadable] 5. Complete the formation of an integrated regional clinical research network at Georgetown University and MedStar Health. [unreadable] [unreadable] The application decribes the substantial research and clinical resources for clinical investigation already available at the member institutions, as well as the recent progress made toward integrating these resources into a robust regional network for clinical research. This integrated regional network will transform the performance of clinical research at these institutions by facilitating investigator access to the largest and most diverse healthcare population in the mid-Atlantic region, which will in turn provide an ideal training ground for newly developed graduate and post-graduate programs in translational and clinical investigation to educate the next generation of clinical investigators. The planning process will be led by a committee of faculty members who are leaders in translational research and clinical research training at the member institutions. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Hyponatremia is the most common electrolyte disorder of hospitalized patients in the U.S. and is a major cause of morbidity and mortality. Most hyponatremic patients are hypoosmolar, reflecting the dilutional basis of this disorder. Because controlled clinical trials are difficult and potentially dangerous in this population, studies using an animal model that mimics the clinical features of dilutional hyponatremia offer the best opportunity to understand the pathophysiology of this disorder. This laboratory has developed such an animal model that we and others have successfully employed to study how the brain adapts to acute and chronic hypoosmolality. Other tissues, particularly the kidney, must adapt to hypoosmolality as well in order for patients to survive this disorder. The most important way in which the kidney adapts is via renal escape from antidiuresis. In animal models of vasopressin (AVP) administration and patients with SlADH, water loading results in initial water retention and progressive hyponatremia, which is then followed by escape from the antidiuresis. Escape is characterized by increased water excretion despite sustained administration of AVP, and allows water balance to be re-established and the serum [Na+] to be stabilized at a steady, albeit decreased, level. Although this phenomenon has been known since the 1950s, there was no consensus regarding the underlying mechanism. We recently discovered that a marked down-regulation of protein and mRNA levels of the water channel, aquaporin-2 (AQP2), correlated temporally with the onset of renal escape from dDAVP-induced antidiuresis. Subsequent studies from our laboratory have strongly implicated down- regulation of AVP V2 receptor (V2R) expression and binding, with subsequent blunted AVP-stimulated cAMP production in kidney collecting duct cells, as a likely cause of the changes in AQP2 expression. The present application proposes to identify the systemic, intrarenal and intracellular mechanisms mediating this response, and specifically the interactions between components of the renin-angiotensin-aldosterone and vasopressin systems both directly, via changes in AVP V2R expression, and indirectly, through changes in systemic blood pressure and the renal microcirculation. These studies will provide a better understanding of the integrative mechanisms, from whole organism hemodynamics to cellular responses, underlying the most basic and clinically important physiological defense that allows patients to survive hypoosmolar disorders.

[unreadable] DESCRIPTION (provided by applicant): [unreadable] [unreadable] Osteoporosis, and resulting osteoporotic fractures, are major health problems in the United States. Whereas age and gonadal hormone deficiency are well known to be major risk factors for osteoporosis, other causes of osteoporosis are increasingly recognized as contributing to accelerated bone loss and increased fracture incidence. Recent studies have found a high frequency of secondary causes of osteoporosis in asymptomatic women with osteoporosis: medication use contributed to bone loss in 53%, hormonal and metabolic abnormalities in 44%, and chronic diseases of the gastrointestinal tract, chronic obstructive pulmonary disease, organ transplantation, autoimmune diseases, genetic diseases, and marrow-based and neoplastic disorders in 18% in aggregate. Consequently, recognition of novel factors leading to osteoporosis is important from both a preventative and a therapeutic perspective. In considering other potential causes of bone loss, clinical cases of unexplained osteoporosis in patients with chronic hyponatremia due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH) prompted us to examine this as another potential cause of accelerated bone loss. Using an animal model of chronic stable hyponatremia developed in this laboratory, the preliminary studies presented in this grant application verify that chronic hyponatremia is associated with severe osteoporosis in both young and aged rats, and suggest a direct effect of low sodium levels to stimulate osteoclast-mediated bone resorption. Moreover, analysis of human data from the Third National Health and Nutrition Examination Survey (NHANES III) showed a significantly increased odds ratio for osteoporosis in the hip among U.S. adults e50 years with hyponatremia compared to those with normal serum sodium levels. In view of the high reported prevalence of hyponatremia in geriatric patients (7-35%) coupled with a recently discovered association between gait instability and falls in patients with even asymptomatic hyponatremia, any additional increased risk of accelerated osteoporosis in this vulnerable aged population would be of great concern. These studies will therefore directly address the hypothesis that hyponatremia represents a previously unrecognized cause of osteoporosis, and is a contributing factor to the high morbidity and mortality from bone disease and fracture in our elderly population.Hyponatremia, or low sodium concentrations in the blood, occurs in 7-35% of geriatric patients. Recently, this disorder has been shown to cause gait instability and an increased incidence of falls in patients. Our preliminary studies have shown that hyponatremia also causes significant bone loss in animals, and is independently associated with an increased risk of osteoporosis in humans. The studies in this grant application will ascertain to what degree hyponatremia is a previously unrecognized cause of osteoporosis, which may contribute to the high morbidity and mortality from bone disease and fracture in our vulnerable elderly population. [unreadable] [unreadable] [unreadable] [unreadable] [unreadable]

The Georgetown-Howard Universities Center for Clinical and Translational Science (GHUCCTS) is a primary partnership of Georgetown University (GU) and Howard University (HU), with 3 affiliated hospital systems and research institutes: MedStar Health and Research Institute (MSH/MRI), Oak Ridge National Laboratory (ORNL), and the Washington, DC Veteran's Affairs Medical Center (WVAMC). This application is a resubmission of a revised previous application from 2008. The specific aims of GHUCCTS are: 1) To speed improvements in human health by stimulating innovative, multidisciplinary, and cross-institutional research among the GHUCCTS investigators; 2) To support the careers of clinical and translational investigators through a wide variety of didactic educational programs coupled with focused mentorship; and 3) To enhance clinical and translational research on underserved populations, both in the Washington DC region and nationally, prominently including minorities, the aged, and the disabled. To accomplish these aims, we will integrate our existing NCRR-funded programs, including two existing MOI-funded GCRCs at GU and HU and our successful multi-institutional K30 program, with a new and innovative hospital, practice- based, laboratory-based, and community-based research infrastructure for clinical and translational science. The new capabilities that we will build as part of GHUCCTS include a coordinated multi-institutional biomedical informatics infrastructure, an expanded clinical research operation that will create new community-based clinical research units, a new community engagement resource component to support and enhance community-based research, expanded resources in regulatory knowledge and support that will be intimately integrated with ethics, and new funded research projects in the development of novel translational methodologies in collaboration with the supercomputing and systems genetics translational capabilities of ORNL. The integration of these clinical and translational resources across the GHUCCTS institutions will be accompanied by a strong research education, training, and career development program that will train a new generation of researchers, including a new Clinical and Translational Scholars K12 program and a new Masters degree program in clinical and translational science. Our innovative approach to collaboration and multi-disciplinary research involving multiple major research-intensive institutions of our region, in collaboration with the national CTSA network, will help our institutions and our community in the Washington, DC area benefit from the generation and application of new discoveries in clinical and translational science. RELEVANCE (See instructions):

This subproject represents an estimate of the percentage of the CTSA funding that is being utilized for a broad area of research (AIDS research, pediatric research, or clinical trials). The Total Cost listed is only an estimate of the amount of CTSA infrastructure going towards this area of research, not direct funding provided by the NCRR grant to the subproject or subproject staff. The Georgetown-Howard Universities Center for Clinical and Translational Science (GHUCCTS) is a primary partnership of Georgetown University (GU) and Howard University (HU), with 3 affiliated hospital systems and research institutes: MedStar Health and Research Institute (MSH/MRI), Oak Ridge National Laboratory (ORNL), and the Washington, DC Veteran's Affairs Medical Center (WVAMC). This application is a resubmission of a revised previous application from 2008. The specific aims of GHUCCTS are: 1) To speed improvements in human health by stimulating innovative, multidisciplinary, and cross-institutional research among the GHUCCTS investigators;2) To support the careers of clinical and translational investigators through a wide variety of didactic educational programs coupled with focused mentorship;and 3) To enhance clinical and translational research on underserved populations, both in the Washington DC region and nationally, prominently including minorities, the aged, and the disabled. To accomplish these aims, we will integrate our existing NCRR-funded programs, including two existing MOI-funded GCRCs at GU and HU and our successful multi-institutional K30 program, with a new and innovative hospital, practice- based, laboratory-based, and community-based research infrastructure for clinical and translational science. The new capabilities that we will build as part of GHUCCTS include a coordinated multi-institutional biomedical informatics infrastructure, an expanded clinical research operation that will create new community-based clinical research units, a new community engagement resource component to support and enhance community-based research, expanded resources in regulatory knowledge and support that will be intimately integrated with ethics, and new funded research projects in the development of novel translational methodologies in collaboration with the supercomputing and systems genetics translational capabilities of ORNL. The integration of these clinical and translational resources across the GHUCCTS institutions will be accompanied by a strong research education, training, and career development program that will train a new generation of researchers, including a new Clinical and Translational Scholars K12 program and a new Masters degree program in clinical and translational science. Our innovative approach to collaboration and multi-disciplinary research involving multiple major research-intensive institutions of our region, in collaboration with the national CTSA network, will help our institutions and our community in the Washington, DC area benefit from the generation and application of new discoveries in clinical and translational science.

This subproject represents an estimate of the percentage of the CTSA funding that is being utilized for a broad area of research (AIDS research, pediatric research, or clinical trials). The Total Cost listed is only an estimate of the amount of CTSA infrastructure going towards this area of research, not direct funding provided by the NCRR grant to the subproject or subproject staff. The Georgetown-Howard Universities Center for Clinical and Translational Science (GHUCCTS) is a primary partnership of Georgetown University (GU) and Howard University (HU), with 3 affiliated hospital systems and research institutes: MedStar Health and Research Institute (MSH/MRI), Oak Ridge National Laboratory (ORNL), and the Washington, DC Veteran's Affairs Medical Center (WVAMC). This application is a resubmission of a revised previous application from 2008. The specific aims of GHUCCTS are: 1) To speed improvements in human health by stimulating innovative, multidisciplinary, and cross-institutional research among the GHUCCTS investigators;2) To support the careers of clinical and translational investigators through a wide variety of didactic educational programs coupled with focused mentorship;and 3) To enhance clinical and translational research on underserved populations, both in the Washington DC region and nationally, prominently including minorities, the aged, and the disabled. To accomplish these aims, we will integrate our existing NCRR-funded programs, including two existing MOI-funded GCRCs at GU and HU and our successful multi-institutional K30 program, with a new and innovative hospital, practice- based, laboratory-based, and community-based research infrastructure for clinical and translational science. The new capabilities that we will build as part of GHUCCTS include a coordinated multi-institutional biomedical informatics infrastructure, an expanded clinical research operation that will create new community-based clinical research units, a new community engagement resource component to support and enhance community-based research, expanded resources in regulatory knowledge and support that will be intimately integrated with ethics, and new funded research projects in the development of novel translational methodologies in collaboration with the supercomputing and systems genetics translational capabilities of ORNL. The integration of these clinical and translational resources across the GHUCCTS institutions will be accompanied by a strong research education, training, and career development program that will train a new generation of researchers, including a new Clinical and Translational Scholars K12 program and a new Masters degree program in clinical and translational science. Our innovative approach to collaboration and multi-disciplinary research involving multiple major research-intensive institutions of our region, in collaboration with the national CTSA network, will help our institutions and our community in the Washington, DC area benefit from the generation and application of new discoveries in clinical and translational science.

This subproject represents an estimate of the percentage of the CTSA funding that is being utilized for a broad area of research (AIDS research, pediatric research, or clinical trials). The Total Cost listed is only an estimate of the amount of CTSA infrastructure going towards this area of research, not direct funding provided by the NCRR grant to the subproject or subproject staff. The Georgetown-Howard Universities Center for Clinical and Translational Science (GHUCCTS) is a primary partnership of Georgetown University (GU) and Howard University (HU), with 3 affiliated hospital systems and research institutes: MedStar Health and Research Institute (MSH/MRI), Oak Ridge National Laboratory (ORNL), and the Washington, DC Veteran's Affairs Medical Center (WVAMC). This application is a resubmission of a revised previous application from 2008. The specific aims of GHUCCTS are: 1) To speed improvements in human health by stimulating innovative, multidisciplinary, and cross-institutional research among the GHUCCTS investigators;2) To support the careers of clinical and translational investigators through a wide variety of didactic educational programs coupled with focused mentorship;and 3) To enhance clinical and translational research on underserved populations, both in the Washington DC region and nationally, prominently including minorities, the aged, and the disabled. To accomplish these aims, we will integrate our existing NCRR-funded programs, including two existing MOI-funded GCRCs at GU and HU and our successful multi-institutional K30 program, with a new and innovative hospital, practice- based, laboratory-based, and community-based research infrastructure for clinical and translational science. The new capabilities that we will build as part of GHUCCTS include a coordinated multi-institutional biomedical informatics infrastructure, an expanded clinical research operation that will create new community-based clinical research units, a new community engagement resource component to support and enhance community-based research, expanded resources in regulatory knowledge and support that will be intimately integrated with ethics, and new funded research projects in the development of novel translational methodologies in collaboration with the supercomputing and systems genetics translational capabilities of ORNL. The integration of these clinical and translational resources across the GHUCCTS institutions will be accompanied by a strong research education, training, and career development program that will train a new generation of researchers, including a new Clinical and Translational Scholars K12 program and a new Masters degree program in clinical and translational science. Our innovative approach to collaboration and multi-disciplinary research involving multiple major research-intensive institutions of our region, in collaboration with the national CTSA network, will help our institutions and our community in the Washington, DC area benefit from the generation and application of new discoveries in clinical and translational science.

This subproject represents an estimate of the percentage of the CTSA funding that is being utilized for a broad area of research (AIDS research, pediatric research, or clinical trials). The Total Cost listed is only an estimate of the amount of CTSA infrastructure going towards this area of research, not direct funding provided by the NCRR grant to the subproject or subproject staff. The Georgetown-Howard Universities Center for Clinical and Translational Science (GHUCCTS) is a primary partnership of Georgetown University (GU) and Howard University (HU), with 3 affiliated hospital systems and research institutes: MedStar Health and Research Institute (MSH/MRI), Oak Ridge National Laboratory (ORNL), and the Washington, DC Veteran's Affairs Medical Center (WVAMC). This application is a resubmission of a revised previous application from 2008. The specific aims of GHUCCTS are: 1) To speed improvements in human health by stimulating innovative, multidisciplinary, and cross-institutional research among the GHUCCTS investigators;2) To support the careers of clinical and translational investigators through a wide variety of didactic educational programs coupled with focused mentorship;and 3) To enhance clinical and translational research on underserved populations, both in the Washington DC region and nationally, prominently including minorities, the aged, and the disabled. To accomplish these aims, we will integrate our existing NCRR-funded programs, including two existing MOI-funded GCRCs at GU and HU and our successful multi-institutional K30 program, with a new and innovative hospital, practice- based, laboratory-based, and community-based research infrastructure for clinical and translational science. The new capabilities that we will build as part of GHUCCTS include a coordinated multi-institutional biomedical informatics infrastructure, an expanded clinical research operation that will create new community-based clinical research units, a new community engagement resource component to support and enhance community-based research, expanded resources in regulatory knowledge and support that will be intimately integrated with ethics, and new funded research projects in the development of novel translational methodologies in collaboration with the supercomputing and systems genetics translational capabilities of ORNL. The integration of these clinical and translational resources across the GHUCCTS institutions will be accompanied by a strong research education, training, and career development program that will train a new generation of researchers, including a new Clinical and Translational Scholars K12 program and a new Masters degree program in clinical and translational science. Our innovative approach to collaboration and multi-disciplinary research involving multiple major research-intensive institutions of our region, in collaboration with the national CTSA network, will help our institutions and our community in the Washington, DC area benefit from the generation and application of new discoveries in clinical and translational science.

This subproject represents an estimate of the percentage of the CTSA funding that is being utilized for a broad area of research (AIDS research, pediatric research, or clinical trials). The Total Cost listed is only an estimate of the amount of CTSA infrastructure going towards this area of research, not direct funding provided by the NCRR grant to the subproject or subproject staff. The Georgetown-Howard Universities Center for Clinical and Translational Science (GHUCCTS) is a primary partnership of Georgetown University (GU) and Howard University (HU), with 3 affiliated hospital systems and research institutes: MedStar Health and Research Institute (MSH/MRI), Oak Ridge National Laboratory (ORNL), and the Washington, DC Veteran's Affairs Medical Center (WVAMC). This application is a resubmission of a revised previous application from 2008. The specific aims of GHUCCTS are: 1) To speed improvements in human health by stimulating innovative, multidisciplinary, and cross-institutional research among the GHUCCTS investigators;2) To support the careers of clinical and translational investigators through a wide variety of didactic educational programs coupled with focused mentorship;and 3) To enhance clinical and translational research on underserved populations, both in the Washington DC region and nationally, prominently including minorities, the aged, and the disabled. To accomplish these aims, we will integrate our existing NCRR-funded programs, including two existing MOI-funded GCRCs at GU and HU and our successful multi-institutional K30 program, with a new and innovative hospital, practice- based, laboratory-based, and community-based research infrastructure for clinical and translational science. The new capabilities that we will build as part of GHUCCTS include a coordinated multi-institutional biomedical informatics infrastructure, an expanded clinical research operation that will create new community-based clinical research units, a new community engagement resource component to support and enhance community-based research, expanded resources in regulatory knowledge and support that will be intimately integrated with ethics, and new funded research projects in the development of novel translational methodologies in collaboration with the supercomputing and systems genetics translational capabilities of ORNL. The integration of these clinical and translational resources across the GHUCCTS institutions will be accompanied by a strong research education, training, and career development program that will train a new generation of researchers, including a new Clinical and Translational Scholars K12 program and a new Masters degree program in clinical and translational science. Our innovative approach to collaboration and multi-disciplinary research involving multiple major research-intensive institutions of our region, in collaboration with the national CTSA network, will help our institutions and our community in the Washington, DC area benefit from the generation and application of new discoveries in clinical and translational science.

Contact PD/PI: VERBALIS, JOSEPH G PROJECT ABSTRACT The Georgetown-Howard Universities Center for Clinical and Translational Science (GHUCCTS) is a primary partnership of Georgetown University (GU) and Howard University (HU), with 3 affiliated hospital systems and research institutes: MedStar Health and Research Institute (MHRI), Oak Ridge National Laboratory (ORNL), and the Washington, DC Veteran's Affairs Medical Center (DCVAMC). The specific aims of GHUCCTS are: 1) to improve the infrastructure that supports high quality interdisciplinary clinical and translational research, both via inter-institutional collaborations between all GHUCCTS institutions as well as multicenter clinical trials across the national CTSA consortium, with increasing levels of speed and efficiency, and to develop innovative computational methods to speed and enhance translation; 2) to continue to develop GHUCCTS as a model of inter-institutional collaboration that leverages the strengths and attributes of its diverse participating institutions to evolve GHUCCTS into regional CTSA hub with unique and synergistic strengths; 3) to leverage our location, expertise and the co-leadership of a minority-serving institution to design and implement research that will have a high impact on underserved populations with health disparities, including minorities, people with disabilities, and elderly populations; 4) to design and disseminate vibrant and innovative educational programs at multiple levels (undergraduate, medical school, graduate, study coordinators, research nurses, and junior faculty) that promote team science and provides the highest quality of career development training for the clinical and translational investigators of the future; and 5) to both draw from and contribute to the collective efforts of the national CTSA consortium to advance each of the Strategic Goals of GHUCCTS, the National Center for Advancing Translational Science (NCATS), and the CTSA national consortium. The integration of multiple clinical and translational resources across the diverse GHUCCTS institutions will be accompanied by a strong research education, training, and career development program that will train a new generation of clinical and translational researchers. Our innovative approaches to collaboration and interdisciplinary research involving multiple major research-intensive institutions of our region, in collaboration with the national CTSA network, will ensure that our institutions and our community in the Washington, DC area benefit maximally from the generation and application of new discoveries in clinical and translational science. Project Summary/Abstract Page 124 Contact PD/PI: VERBALIS, JOSEPH G

PROJECT SUMMARY/ABSTRACT Osteoporosis, and resulting osteoporotic fractures, are major health problems in the world. Age and gonadal hormone deficiency are well known to be major risk factors for osteoporosis, but other causes of osteoporosis are increasingly recognized as contributing to accelerated bone loss and increased fracture incidence. Consequently, recognition of novel factors leading to osteoporosis is important from both a preventative and a therapeutic perspective. In considering other potential causes of bone loss, clinical cases of unexplained osteoporosis in patients with chronic hyponatremia due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH) prompted us to examine this as another potential cause of accelerated bone loss. Using an animal model of SIADH developed in this laboratory, we have shown that chronic hyponatremia causes severe resorptive bone loss in young and old rats, both male and female. Our in vivo studies have indicated a direct effect of low extracellular sodium levels to stimulate osteoclastogenesis and activate osteoclast-mediated bone resorption. Additional studies in hyponatremic animals have documented damage to other organs, including testis, heart and skeletal muscle that resemble age-related senescent changes in these organs. In view of the very high reported prevalence of hyponatremia in geriatric patients (7-35%) coupled with an association between gait instability and falls with even asymptomatic hyponatremia, any additional hyponatremia-related increased risk of accelerated osteoporosis in this vulnerable aged and frail population would be of much concern. The importance of hyponatremia for bone health has now been corroborated by multiple retrospective clinical studies that have shown a significant association between even mild hyponatremia and increased bone fractures, and our epidemiological studies of 2.9 million patients that indicate odds ratios for both osteoporosis and fragility fractures of 11.2-12.1 in patients with chronic sustained hyponatremia. The proposed studies will address the cellular and molecular mechanisms by which hyponatremia increases bone fragility, the reversibility of hyponatremia-induced bone loss and gait instability, and the best treatments to prevent and/or reverse hyponatremia-induced bone and brain dysfunction using interventions specifically targeted to cellular mechanisms that we have already discovered during previous NIH funding of this project.

PROJECT ABSTRACT In the U.S., from 2011 to 2014, 7,208 maternal fatalities, with the trend worsening year-on-year (CDC, 2016). In addition to the 700+ fatalities, at least 50,000 woman experienced life-threatening complications, annually. According to CDC (2019) for every fatality, 70 more women suffer avoidable, traumatic complications as a result of pregnancy. Medstar Health Research Institute and Invaryant, Inc, propose the evaluation of a cardiac risk assessment tool for pregnant and postpartum women; this tool updates automatically directly from patient medical records; wearable devices; and patient surveys. Success implies disruptive improvement in women's health. Proposed research involves three key elements: technology, data, and social determinants of health (SDOH) using geospatial mapping of patient locations. Technology: Study technology shall be based on the Invaryant Health Platform (IHP), a technology that automatically ingests data, from medical records, wearable devices, and other sources using proprietary AI based interoperability technology called Mesh-Complex Method Exchange (Mesh-CMX). We propose using the IHP in conjunction with novel prototype-level technology, namely Healthy Outcomes for all Pregnancy Experiences-Cardiovascular-risk Assessment Technology (HOPE-CAT) and the Invaryant machine learning technologies to monitor the patient, based on signals, out-of-range ?trip-wires?, and trends in the mother's health data that merit medical intervention. By extending the proof of concept into an early commercial version of the software, and integrating it to the IHP which will automatically update changes in the patient's medical record, we will provide an ?early warning? system for mothers and their providers. Data: The study will be tested on patients' medical records using the MedStar's Analytics Platform (MAP), a registry of over 5 Million unique patients. The tool will subsequently have the potential to be leveraged to over 90 million medical records for the MedStar and Cerner hospital systems, distilled down to meet specific eligibility criteria including, gender, age, race, pregnancy and medical outcomes. A second phase of this project would take the findings from the retrospective study (this grant request) and use the technology within the Medstar hospital system, to validate the efficacy of the findings in a ?real-world setting?. Using our proprietary AI technology, we will compare each mother's progress against a cohort of retrospective data to enhance diagnostics and provide real-time feedback to caregivers and patients. Geospatial mapping: Mapping the patient medical record and the health information to their social setting is vital for understanding the underlying social constructs that affect the health of mothers in different regions.

Abstract A major challenge to full utilization the available data and resources has been the complex nature of health data, and heterogeneity of data sources (including unstructured clinical notes) combined with a lack of standards. The lack of standards precludes semantic interoperability across platforms and between institutions. Instead, current approaches utilize resource intensive natural language processes to extract, transform, and correlate data from different sources for analysis. To improve translational science and accelerate research to improve patient outcomes, many new and innovative studies are leveraging large volumes of available data through standardized and shared data initiatives. With current advances in computing and health data analysis tools, methods and access, and to make data more meaningful, open, and accessible, research studies have moved beyond traditional retroactive reporting to pragmatic interventions and predictive capabilities. Ongoing efforts focus on exploiting common data standards and models such as the Observational Medical Outcomes Partnership (OMOP) standard?de?ned by the Observational Health Data Sciences and Informatics (OHDSI) consortium, and accepted as canon by both the NIH and PCORI? will lead the way to discover insights in textual narrative, enforce data standardization, and promote scalability and sharing. The OHDSI Common Data Models (CDM) makes data more meaningful, open, and accessible, which drives translational science and allows for consistent development of predictive models across different data sources. The National COVID Cohort Collaborative (N3C), ACT, BD2K-NIH Data Commons, the National Center for Data to Health (CD2H), and others are among the efforts that will lead to new discoveries and informed decision making, driven by data science and undergirded by mature Big Data technologies. We propose to design and establish novel, scalable, and standardized big data processes to massively abstract the raw electronic medical record datasets for observational studies. This project will develop a secure cloud-based environment to host these data, as well as the application programming and graphical user interfaces to support observational research studies leveraging these resources. By these means we will reduce the barriers to data standardization, annotation and sharing for reproducible analytics and begin to enforce complete semantic and syntactic interoperability between the resources in the data ecosystem. This effort will enable our investigators to study the effects of medical interventions and predict patients' health outcomes and generate the empirical evidence base necessary to establish best practices in observational analysis.