John E Hall - US grants

The overall objective of this proposal is to develop a quantitative systems analysis of the long-term importance of the renin-angiotensin system (RAS), kallikrenin-kinin system, renal prostaglandins (PG's), and adrenocortical hormones in regulating renal hemodynamics, electrolyte excretion, body fluid volumes, and arterial pressure. Since there is very little quantitative information available on the long-term effects of these hormones on renal function in intact conscious animals, all of the proposed studies will be conducted in intact conscious dogs. The effectiveness of these hormonal systems in regulating renal function after various perturbations such as changes in salt and water intake or changes in renal artery pressure will be quantitated in normal intact dogs (closed-loop feedback conditions) and in dogs where one or more of the hormonal feedbacks have been interrupted (open-loop feedback conditions) by surgical techniques (i.e., adrenalectomy) and chemical methods (i.e., infusion of angiotensin converting enzyme inhibitors, PG synthetase inhibitors, and by chronic iv infusion of angiotensin II, PG's, glucocorticoids, and mineralocorticoids). Changes in renal function after these perturbations will be quantitated with techniques recently developed in our laboratory which allow us to accurately estimate glomerular filtration rate and effective renal plasma flow day after day for long periods of time without disturbing the animal and without repeated bladder catheterizations. Also techniques developed for continuous recording of blood pressure 24 hours a day, continuous intravenous infusions, and for measurement of other indices of renal and endocrine function will be utilized in these studies. Since essentially all of the experiments will be conducted over a period of several days or weeks in conscious animals, we believe that these studies will provide us with reliable quantitative data which will be invaluable in developing a systems analysis of the importance of these hormonal systems in regulating renal function as well as body fluid volumes and arterial pressure.

The main objective of this proposal is to test the hypothesis that hyperinsulinemia, comparable to that found in obese hypertensives, any cause chronic hypertension via alterations in renal function. Our studies will focus mainly on the possibility that the hyperinsulinemia initiates hypertension by increasing renal tubular sodium reabsorption, similar to the effect of mineralocorticoids. Our approach will employ animal experimentation, studies in humans, and a theoretical analysis of the effects of insulin on renal function and arterial pressure. The animal experiments are designed to determine whether there is a cause and effect relationship between chronic hyperinsulinemia in dogs with normal kidneys and with various degrees of functional renal reserve, caused by reduced renal mass or increased sodium intake. Studies are also designed to evaluate the importance of changes in activity of the renin-angiotensin system (RAS), aldosterone, the sympathetic nervous system, and atrial natriuretic factor (ANF) in modulating insulin-sodium-blood pressure interrelationships. The relative importance of the direct intrarenal and extrarenal actions of insulin in causing chronic hypertension will also be quantitated. And finally, these studies will evaluate the intrarenal mechanisms, including changes in renal hemodynamics and tubular reabsorption, by which insulin influences renal excretion chronically and the role of extrarenal mechanisms, such as the RAS, aldosterone, the sympathetic nervous system, and ANF in modulating insulin's renal actions. All of these studies will be conducted in chronically instrumented conscious dogs using techniques recently developed in our laboratory that allow us to accurately estimate changes in renal function and systemic hemodynamics for along periods of time. The clinical studies are designed primarily to determine whether insulin resistance, which occurs in peripheral tissues of obese hypertensives, also occurs in the renal tubule. In these experiments, the effects of insulin on renal sodium reabsorption will be evaluated in normotensive and hypertensive non-obese and obese individuals. A systems analysis of the interrelationships between insulin, body fluid homeostasis, and arterial pressure regulation will be developed. The experiments will provide much of the quantitative data needed to develop this analysis and the mathematical analysis will, in turn, be important in evaluating the validity of our hypotheses and in suggesting new areas for experimentation.

DESCRIPTION (Provided by applicant): A major long-term goal of this Program Project Grant (PPG) has been to develop a quantitative systems analysis of cardiovascular (CV) dynamics and related control systems, including the kidneys, the sympathetic nervous system (SNS), endothelial factors, and the endocrine system. Our experimental studies have focused on understanding the basic molecular and physiological control mechanisms of each component of the circulation, the feedback systems that coordinate these components, and integration of this information into a composite systems analysis of CV regulation. Another key objective has been to translate our research on basic mechanisms of CV control to understanding the pathophysiology of disorders such as hypertension (HT). The current focus of the PPG is on neurohumoral, endothelial, and intrarenal mechanisms that contribute to impaired pressure natriuresis and increased blood pressure (BP) in experimental models that are highly relevant to common, and difficult to treat, forms of human HT caused by obesity, preeclampsia, and postmenopausal hyperandrogenemia. Four unique features of this program are: 1) it utilizes an integrative approach to understand complex interactions between multiple components of CV control systems; 2) it focuses mainly on long-term control of the circulation because many CV diseases, such as HT, are manifestations of abnormal control mechanisms that develop slowly over long periods of time; 3) it utilizes unique experimental models that mimic common forms of human HT, including obesity, preeclampsia, and postmenopausal-induced HT; 4) it uses mathematical modeling and systems analyses to provide a conceptual framework for understanding cardiovascular dynamics and renal, endothelial, hormonal and neural mechanisms of HT. The research proposed in this application is described by the titles of the projects as follows: I. Neurohumoral and Renal Mechanisms of Hypertension: this project will elucidate the neurohumoral mechanisms, central nervous system (CNS) circuits and signaling pathways that mediate obesity induced SNS activation, impaired renal-pressure natriuresis, and HT as well as regulation of energy balance and metabolism; II. Endothelial Factors, the Kidney and Hypertension: this project will determine the role of obesity in altering multiple factors released by the placenta that cause endothelial dysfunction, impaired renal-pressure natriuresis, and HT during chronic reductions in uterine perfusion pressure in pregnancy. III. Hormonal and Intrarenal Mechanisms of Postmenopausal Hypertension: this project will determine the role of increased SNS activity, CNS signaling pathways, and intrarenal mechanisms that increase renal vascular resistance, blunt pressure natriuresis and raise BP in postmenopausal HT associated with hyperandrogenemia. The total program, including core support services, provides a unique interdisciplinary approach toward developing an integrative analysis of long-term regulation of BP and circulatory dynamics in forms of experimental HT that have great relevance to human HT.

The neurohumoral systems and kidneys are closely linked in long-term control of cardiovascular dynamics. Our previous studies have suggested that abnormal kidney function, manifested by impaired pressure natriuresis, plays a key role in all forms of chronic hypertension studied thus far. Some abnormalities of pressure natriuresis originate intrarenally, but many occur through activation of neurohumoral mechanisms that impair renal excretory capability. For this reason, a major part of our research program has been directed toward understanding the neurohumoral and intrarenal mechanisms that regulate kidney function, and how these are altered in chronic hypertension. During the previous project period, we investigated the mechanisms of obesity hypertension, which has special relevance to human essential hypertension. Our studies indicate that activation of the sympathetic nervous system (SNS), via the renal nerves, plays a major role in the pathophysiology of obesity-hypertension. The proposed studies will examine novel mechanisms that may contribute to activation of the SNS and hypertension as well as regulation of food intake and metabolism in obesity. The central hypothesis of this proposal is that excess adiposity increases circulating leptin which acts on the hypothalamus to stimulate the proopiomelanocortin (POMC) pathway and melanocortin 3/4-receptors (MC3/4-R) which, in turn, causes increased renal SNS activity, impaired pressure natriuresis, and hypertension. We will use chronically instrumented rats, MC4-R knockout mice, and chronically instrumented obese dogs in these studies since each species has certain advantages in testing the overall hypothesis. Chronically instrumented rats will be used in conjunction with specific pharmacological agonists of the MC3/4-R to test the hypothesis that chronic activation of the MC3/4-R raises arterial pressure via increased renal SNS activity. We will also use specific antagonists of the MC3/4-R to test the hypothesis that hyperleptinemia increases arterial pressure by activating the MC3/4-R, and that chronic blockade of the MC3/4-R causes obesity but little or no impairment of pressure natriuresis or increased arterial pressure. The MC4-R knockout mouse model will be used to provide a non-pharmacologic means of testing whether the absence of a functional MC4-R attenuates or abolishes the chronic effects of obesity or hyperleptinemia to raise arterial pressure. The obese dog model will be used to test the hypothesis that a functional hypothalamic MC3/4-R is necessary for dietary-induced obesity to increase SNS activity, impair pressure natriuresis, and raise arterial pressure since this model closely mimics obesity-hypertension in humans. This model also permits extensive investigation of the hemodynamic, renal, endocrine, and metabolic mechanisms that mediate increased blood pressure during the development of obesity or changes in activity of the leptin-POMC pathways. The use of multiple species not only permits us to effectively test the overall hypothesis, but also provides a greater assurance that our results have broad applicability.

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The neurohumoral systems and kidneys are closely linked in long-term control of cardiovascular dynamics. Our previous studies provided evidence that abnormal kidney function, manifested by impaired pressure natriuresis, plays a key role in all forms of chronic hypertension studied thus far. Some abnormalities of pressure natriuresis originate intrarenally, but many occur through activation of neurohumoral mechanisms that impair renal excretory capability. For this reason, a major part of our research program has been directed toward understanding the neurohumoral and intrarenal mechanisms that regulate kidney function and how these are altered in chronic hypertension. Our recent work has focused on the mechanisms of obesity hypertension which has special relevance to human essential hypertension. We provided evidence that activation of renal sympathetic nerve activity (RSNA) plays a major role in the pathophysiology of obesityhypertension. We also found that leptin, a cytokine released from adipocytes, contributes to sympathetic nervous system (SNS) activation and increased blood pressure (BP) mainly by stimulating the central nervous system (CMS) pro-opiomelanocortin (POMC) pathway. However, the CMS circuits and cell signaling mechanisms that mediate the chronic effects of the leptin-melanocortin system on RSNA, BP, and metabolism are poorly understood. The central hypothesis of this proposal is that leptin-melanocortin activation in distinct areas of the brain and through multiple intracellular signaling pathways can differentially and independently regulate appetite, oxygen consumption (VOz) and energy expenditure, RSNA and BP. Specific Aim 1 will determine the role of leptin receptors in the forebrain, POMC and paraventricular (PVN) neurons in constitutive regulation of metabolic and cardiovascular functions and in mediating the chronic actions of leptin on control of appetite, V02 and energy expenditure, RSNA, and BP. Specific Aim 2 will determine the specific roles of Stat3, Shp2-MAPK, and lrs2-PI3K signaling in the forebrain, POMC and PVN neurons in constitutive regulation of metabolic and cardiovascular functions and in mediating the chronic appetite suppression, VO2 and energy expenditure, RSNA, and BP actions of leptin. Specific Aim 3 will determine the role of melanocortin 4 receptor (MC4R) activation in the forebrain and PVN neurons in controlling metabolic and cardiovascular functions, and in mediating the chronic appetite suppression, VO2 and energy expenditure, RSNA, and BP actions of leptin. These studies will use novel mouse models in which the leptin receptor or the 3 main leptin signaling pathways (StatS, lrs2-PI3K, and Shp2-MAPK) are deleted by Cre/loxP recombinase in the forebrain, POMC or PVN neurons or in the entire brain to determine the brain regions and cell signaling mechanisms that mediate the chronic actions of leptin, and that constitutively control body weight, total body VO2 and energy expenditure, glucose homeostasis, RSNA and BP. The role of MC4R activation in specific CNS regions in mediating the chronic actions of leptin will be determined in mice with mutated MC4R (loxTB-MC4R"''mice) where the MC4R is "rescued" in the forebrain, POMC or PVN neurons, or the entire brain. Integrative physiological methods, including 24 hr/day monitoring of BP, RSNA, kidney function, and metabolic functions, in combination with unique genetic models provide a novel and powerful approach to elucidate the complex CNS circuits and signaling pathways by which the leptin-melanocortin system differentially regulates BP, sympathetic activity and metabolic functions that determine energy balance.

DESCRIPTION (provided by applicant): Cardiovascular, renal and metabolic diseases are inextricably linked and are the leading causes of mortality and morbidity in the United States, especially in Mississippi which has the highest prevalence in the nation of these diseases. These disorders usually cluster together and are highly interdependent. Obesity and associated metabolic disorders, such as diabetes, are major causes of cardiovascular and renal disease. Abnormal kidney function is an important cause as well as a consequence of hypertension, a key risk factor for cardiovascular diseases such coronary artery disease and stroke. Understanding the complex relationships among cardiovascular, renal, and metabolic disorders and developing new therapeutic approaches requires a paradigm shift in research that incorporates multidisciplinary integrated approaches, combining the efforts of basic, clinical and population scientists. A major objective of this proposal is to develop an internationally recognized Cardiorenal and Metabolic Diseases Research Center (CMDRC) that brings together a multidisciplinary group of basic, clinical and population scientists working on a common synergistic theme, and to facilitate their collaborations. The specific aims are: 1) To develop infrastructure and core facilities that foster excellence in basic, clinical, and population research in cardiorenal and metabolic diseases and increase competitiveness of junior investigators for independent funding from NIH and other national biomedical research programs.; 2) To develop mentoring and education programs and research support for promising junior investigators so that they can become productive, independent investigators who can successfully compete for NIH funding; 3) To achieve the specific aims of the research projects described by the junior investigators in this proposal, and to foster their career development; 4) To develop a pipeline of diverse predoctoral graduate students, medical students and postdoctoral fellows trained in cutting edge cardiorenal and metabolic diseases research so they become the next generation of researchers in this field; major emphasis will be placed on recruiting and mentoring underrepresented minority investigators through partnerships with local minority institutions; 5) To enhance collaborations and interactions among established investigators from multiple disciplines in cardiorenal and metabolic diseases at UMMC, as well as with external partners; 6) To strengthen cardiorenal and metabolic disease research at UMMC by recruiting new faculty with expertise in clinical and translational research and in emerging technologies, such as in vivo imaging, molecular genetics, bioinformatics, and systems analysis.

CORE A - ADMINISTRATIVE CORE SUMMARY/ABSTRACT The main purpose of Core A is to provide essential administrative support for all program-related activities and to interface with the National Institutes of Health, the University of Mississippi Medical Center (UMMC) administration, the UMMC Grants and Contracts office, the Department of Physiology and other departments represented in the Program Project Grant (PPG), and the investigators of the PPG. The Program Director is responsible for the scientific and financial management of the program and will be assisted by the Co-Director. The administrative staff of Core A is responsible for purchasing and fiscal management, preparation of manuscripts and posters for national meetings, interfacing with UMMC Human Resources department on personnel issues, program-related travel by the investigators and visits by invited consultants and speakers, and reports to the National Institutes of Health. The Administrative Core also disseminates important information to the program investigators, organizes scientific meetings and seminars related to the PPG, and coordinates assessment of research progress by the Internal and External Advisory Committees. The members of the Internal Advisory Board are leaders of major academic units at UMMC and will assess progress and review the direction of the PPG on a regular basis and will help develop strong liaisons between PPG investigators and key clinical and basic science departments. The External Advisory Board consists of outstanding scientists from other institutions who have expertise that will help advance the goals of the PPG; they will provide periodic assessment of the PPG scientific progress and meet with PPG investigators and the Internal Advisory Board each year. The Administrative Core has centralized many of the day to day business and administrative operations, improving the efficiency and cost-effectiveness of the PPG.

PROJECT I - NEUROHUMORAL AND RENAL MECHANISMS OF HYPERTENSION PROJECT SUMMARY/ABSTRACT Although impaired renal-pressure natriuresis occurs in all forms of chronic hypertension studied thus far, neurohumoral mechanisms often mediate abnormal kidney function and increased blood pressure (BP). Therefore, our research is directed toward understanding neurohumoral mechanisms that alter kidney function in hypertension caused by excess weight gain which accounts for 65-75% of human essential hypertension. We previously demonstrated that increased sympathetic nervous system (SNS) activity plays a major role in the pathophysiology of obesity-hypertension mainly by stimulation of renal sympathetic nerve activity (RSNA). We also found that leptin, an adipocyte derived hormone, contributes to SNS activation and increased BP in obesity by stimulating CNS pro-opiomelanocortin (POMC) neurons and ultimately by activation of melanocortin 4 receptors (MC4R). Our studies also indicate that the CNS POMC-MC4R pathway is a key means by which leptin regulates glucose homeostasis. Moreover, POMC activation can regulate BP and glucose independent of its effects to reduce appetite. The complex CNS circuits that mediate this differential control of cardiovascular and metabolic functions are still poorly understood. In addition, we found that the POMC-MC4R pathway may be important for BP regulation independent of leptin. The central hypothesis of this proposal is that POMC-MC4R activation in distinct areas of the hypothalamus, brainstem and spinal cord can differentially and independently regulate BP, RSNA, and metabolic functions, including appetite and energy expenditure. The proposed studies will determine which specific brain regions are most important in mediating the chronic effects of POMC-MC4R activation on RSNA, baroreflexes and BP regulation, food intake and energy expenditure, as well as the cardiometabolic responses to leptin. We will also determine the role of suppressor of cytokine signaling-3 (SOCS3) and protein tyrosine phosphatase 1B (PTP1B), in modulating leptin's actions on POMC and other neurons of the forebrain, brainstem and spinal cord in regulating cardiometabolic functions. These studies will employ unique, genetically engineered mouse models that permit us to delete or rescue MC4R, SOCS3, or PTP1B in specific neuronal populations of the hypothalamus, brainstem and spinal cord. Sophisticated physiological techniques that provide computerized chronic monitoring of cardiovascular, renal and metabolic functions, coupled with novel animal models, will permit us to unravel the specific CNS circuits by which the POMC-MC4R pathway differentially controls metabolic and cardiovascular functions, and the role of SOCS3 and PTP1B in modulating this system in obesity.

DESCRIPTION (Provided by applicant): A major long-term goal of this Program Project Grant (PPG) has been to develop a quantitative systems analysis of cardiovascular (CV) dynamics and related control systems, including the kidneys, the sympathetic nervous system (SNS), endothelial factors, and the endocrine system. Our experimental studies have focused on understanding the basic molecular and physiological control mechanisms of each component of the circulation, the feedback systems that coordinate these components, and integration of this information into a composite systems analysis of CV regulation. Another key objective has been to translate our research on basic mechanisms of CV control to understanding the pathophysiology of disorders such as hypertension (HT). The current focus of the PPG is on neurohumoral, endothelial, and intrarenal mechanisms that contribute to impaired pressure natriuresis and increased blood pressure (BP) in experimental models that are highly relevant to common, and difficult to treat, forms of human HT caused by obesity, preeclampsia, and postmenopausal hyperandrogenemia. Four unique features of this program are: 1) it utilizes an integrative approach to understand complex interactions between multiple components of CV control systems; 2) it focuses mainly on long-term control of the circulation because many CV diseases, such as HT, are manifestations of abnormal control mechanisms that develop slowly over long periods of time; 3) it utilizes unique experimental models that mimic common forms of human HT, including obesity, preeclampsia, and postmenopausal-induced HT; 4) it uses mathematical modeling and systems analyses to provide a conceptual framework for understanding cardiovascular dynamics and renal, endothelial, hormonal and neural mechanisms of HT. The research proposed in this application is described by the titles of the projects as follows: I. Neurohumoral and Renal Mechanisms of Hypertension: this project will elucidate the neurohumoral mechanisms, central nervous system (CNS) circuits and signaling pathways that mediate obesity induced SNS activation, impaired renal-pressure natriuresis, and HT as well as regulation of energy balance and metabolism; II. Endothelial Factors, the Kidney and Hypertension: this project will determine the role of obesity in altering multiple factors released by the placenta that cause endothelial dysfunction, impaired renal-pressure natriuresis, and HT during chronic reductions in uterine perfusion pressure in pregnancy. III. Hormonal and Intrarenal Mechanisms of Postmenopausal Hypertension: this project will determine the role of increased SNS activity, CNS signaling pathways, and intrarenal mechanisms that increase renal vascular resistance, blunt pressure natriuresis and raise BP in postmenopausal HT associated with hyperandrogenemia. The total program, including core support services, provides a unique interdisciplinary approach toward developing an integrative analysis of long-term regulation of BP and circulatory dynamics in forms of experimental HT that have great relevance to human HT.

PROJECT SUMMARY. The proposed Mississippi Center for Clinical and Translational Research (CCTR) is intended to promote multi-disciplinary and multi-institutional clinical and translational research projects, focused on obesity and related conditions, and involving three Mississippi Institutions?the University of Mississippi Medical Center, Tougaloo College, and the University of Southern Mississippi. This will be done in collaboration with the IDeA-funded Louisiana Clinical and Translational Science Center and the Mayo Clinic Center for Clinical and Translational Science. The CCTR's Professional Development Core will provide extensive training and resources to foster the growth of Mississippi's next generation of obesity investigators and to increase their number, diversity, and success. An Investigator Development Program will provide structured mentorship, training, protected research time, and substantial research support to promising obesity-focused early stage research faculty from all CCTR partner institutions. A Mentor Academy will be provided to train funded, mid-career faculty members to be more effective research and career mentors. An annual, two-week residential Community Engaged Research (CEnR) Institute will train selected junior faculty members from all major Mississippi universities in the principles and practice of CEnR, and will offer opportunities for them to compete for substantial funding for obesity-related pilot research projects. A multi- institutional CEnR Working Group will hold bi-weekly teleconferences to present ongoing and completed CEnR research, discuss available resources and research options, and seek opportunities for multi-institutional obesity research projects and funding. Finally, a CCTR Seminar Series will offer bi-weekly seminars as a forum for the presentation of high-impact obesity-related research and as an opportunity for junior investigators to present their research and receive feedback. The programs described above will create a rich intellectual environment, promote investigator interactions, and provide targeted research investments to increase research collaboration among CCTR investigators from diverse backgrounds and academic disciplines, and to foster the development of young, obesity-focused investigators with sustained, independent extramural funding.

CORE A ? ADMINISTRATIVE, MENTORING AND EDUCATION CORE SUMMARY/ABSTRACT The Cardiorenal and Metabolic Diseases Research Center (CMDRC) has diverse functions and is comprised of multiple components, including research projects of 4 investigators, a Pilot Grants Program, a Mentoring and Education Program, administrative units, and two Research Resources Cores. Core A provides administrative support and coordinates all Center activities, develops and implements mentoring and education programs, and interfaces with the NIGMS, University of Mississippi Medical Center (UMMC) administration, the UMMC Grants and Contracts office, the departments represented in the CMDRC, and the investigators and trainees of the Center. Specific functions of Core A are: 1) to provide leadership for enhancement of infrastructure, mentoring programs, and core facilities that foster research excellence and lead to development of an internationally recognized CMDRC; 2) to develop, implement and monitor a Mentoring and Education Program that facilitates progress of the research projects and development of the junior/early career investigators (ECI) into independent, funded researchers who are also effective collaborators on multidisciplinary research teams; 3) to further enhance the Pilot Grants Program for promising new investigators, with emphasis on recruiting and mentoring underrepresented minority (URM) investigators; 4) to further develop and implement educational programs that facilitate collaborations and interactions among investigators from multiple disciplines at UMMC, as well as with external partners; 5) to develop and implement programs for recruiting, training, and mentoring a diverse group of postdoctoral fellows, undergraduate and graduate student trainees to become the next generation of CMDRC researchers; 6) to provide formative and summative evaluation strategies for progress and effectiveness of all CMDRC programs and Cores; 7) to provide high-level program administrative support to the research project and pilot grant investigators and core directors; 8) to provide fiscal oversight of all research projects and cores and central services for purchasing; 9) to further develop and maintain the CMDRC website, provide assistance to investigators in design and operation of their computer systems, insure that all data and documents are securely stored on the server and on external drives, install new software and make minor repairs of computer equipment for CMDRC investigators; 10) to develop and implement mechanisms for effective communication among the Center investigators, Core leaders, Center staff, External Advisory Board (EAB), Internal Advisory Board (IAB), and Executive Committee, other centers within UMMC, and external partner institutions; 11) to organize scientific meetings and seminars related to the CMDRC as well as meetings of the EAB, IAB, and Executive Committee, and an annual retreat/symposium; 12) to ensure that all CMDRC programs, initiatives, policies and reporting mechanisms are optimally developed, implemented, and administered within federal granting agency policies and deadlines.

OVERALL PROJECT SUMMARY/ABSTRACT Cardiovascular (CV), renal and metabolic diseases are inextricably linked and are the leading causes of mortality and morbidity in the U.S., especially in Mississippi which has the highest prevalence in the nation of these diseases. Cardiorenal and metabolic disorders usually cluster together and are highly interdependent. Obesity and associated metabolic disorders, such as diabetes, are major causes of CV and renal disease. Abnormal kidney function is an important cause as well as a consequence of hypertension, a key risk factor for CV diseases such coronary artery disease and stroke. Understanding the complex relationships among CV, renal, and metabolic disorders and developing new therapeutic approaches requires a paradigm shift in research that incorporates multidisciplinary integrated approaches, combining the efforts of basic, clinical and population scientists. A major objective of this Phase 2 COBRE proposal is to further develop a leading Cardiorenal and Metabolic Diseases Research Center (CMDRC) that brings together a multidisciplinary group of basic, clinical and population scientists working on a common synergistic theme, and to facilitate their collaborations. The specific aims are: 1) to further develop infrastructure and core facilities that foster excellence in basic, clinical, and population research in cardiorenal and metabolic diseases and increase competitiveness of CMDRC investigators for independent funding from NIH and other national biomedical research programs; 2) to enhance CMDRC mentoring and education programs and research support for promising new investigators so that they can become productive, independent investigators who are also effective collaborators on multidisciplinary research teams; 3) to achieve the specific aims of the research projects described by Junior Investigators in this proposal, and to foster their career development; 4) to further develop a pipeline of diverse postdoctoral fellows, graduate and undergraduate students trained in cutting edge cardiorenal and metabolic diseases research so they become the next generation of researchers in this field; major emphasis is placed on recruiting and mentoring underrepresented minority investigators through partnerships with local institutions and by leveraging training programs at UMMC; 5) to enhance collaborations and interactions among established investigators from multiple disciplines in cardiorenal and metabolic diseases at UMMC, other IDeA supported programs, and external partners; 6) to strengthen cardiorenal and metabolic disease research at UMMC by recruiting new faculty with expertise in clinical and translational research, and in emerging technologies (e.g. in vivo imaging, bioinformatics, and systems analysis) and in areas where there are gaps in CMDRC expertise.