2013 — 2017 |
Rahmouni, Kamal |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Role of Brain Bardet-Biedl Syndrome Genes in Metabolic and Cardiovas Regulation
Bardet-Biedl syndrome (BBS) is an autosomal, recessive, heterogeneous human disorder characterized by a pleiotropic phenotype including eariy onset obesity, hypertension and cardiovascular disease. Although BBS is a rare Mendelian disorder, identifying the underiying mechanisms of the phenotypes associated with this syndrome has garnered great interest because the pathophysiology of the phenotypes such as obesity and hypertension in BBS may yield clues to understanding common human obesity and hypertension. Our preliminary data obtained using a series of novel mouse models that phenocopy human BBS point to the importance of the neurogenic mechanisms for the metabolic and cardiovascular dysregulations associated with BBS. Indeed, we identified an intrinsic hypothalamic leptin resistance as a major cause of energy imbalance and obesity in BBS. Our data also indicate that neural mechanisms play a major pathophysiological role in the hypertension associated with deletion of Bbs genes in mice. More recently, we found that CNS deletion of Bbsl gene (using a novel conditional Bbsl flox/flox mouse model) recapitulates the obesity phenotype associated with BBS highlighting the importance of Bbs genes in the central nervous for energy homeostasis. Moreover, Bbs-deficiency causes defects in ER stress and activation of the renin-angiotensin system in the brain. Based on these findings, we hypothesize that Bbs genes in the central nervous system are critical for energy homeostasis and the autonomic regulation of arterial pressure. We plan to test our central hypothesis by pursuing the following 3 hypotheses: 1) Neuronal BBS proteins are important for metabolic and cardiovascular regulation, and disruption of the Bbsl gene in specific neuronal populations alters energy homeostasis, autonomic function and arterial pressure; 2) Defects in the brain BBSome, receptor trafficking, ER stress, and the brain renin-angiotensin system are critically involved in the metabolic, autonomic and arterial pressure alterations associated with BBS; and 3) Haploinsufficiency of Bbs genes increases susceptibility to obesity, autonomic dysfunction and hypertension. RELEVANCE (See instructions): These studies are significant because they will provide important insight into the role of neuronal Bbs genes and identify new fundamental mechanisms underiying the regulation of metabolic and cardiovascular functions by Bbs genes in the central nervous system. The novel information gained from these studies will have potential implications for the management of obesity and associated cardiovascular disorders in BBS as well as in common human obesity.
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2018 — 2021 |
Rahmouni, Kamal |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Neuronal Mechanisms of Obesity and Hypertension: Role of the Bbsome
Abstract: Obesity which has become common in the United States is a major cause of hypertension, a principal reversible risk factor for cardiovascular disease. However, the mechanisms underlying the relationship between obesity and hypertension remain largely unknown. The goal of this proposal is to identify the neuronal and molecular processes that control energy homeostasis and blood pressure and how dysregulation in these processes contribute to obesity and obesity-associated hypertension. This proposal is based on our recent work demonstrating the importance of neuronal Bardet Biedl syndrome (BBS) proteins in the regulation of energy homeostasis and blood pressure. We discovered that the BBSome, a complex of eight BBS proteins, is required for the trafficking of receptors that underlie neural control of energy homeostasis. We further hypothesize that defects in the hypothalamic BBSome contribute to common dietary obesity and associated increase in sympathetic nerve activity and blood pressure. This is supported by our recent intriguing preliminary data implicating dysfunction of the BBSome in the hypertensive high fat diet-induced obese mice. To test our hypothesis, we will investigate whether restoring the BBSome in the hypothamus of diet-induced obese mice alleviate the increased adiposity, energy imbalance, activation of the brain renin-angiotensin system and the increase in blood pressure and sympathetic nerve activity. We will also determine the cellular processes underlying the BBSome-mediated trafficking of the receptors regulating energy homeostasis and use chemogenetics to assess the specificity and extend of the defects caused by disruption of the BBsome in hypothalamic neurons. These innovative studies which will employ unique and sophisticated genetic strategies, neuro-techniques and physiologic approaches should unravel novel mechanisms that underlie obesity and obesity-associated cardiovascular risks, making our work of high clinical relevance. Insights into the cellular and molecular processes that control energy balance and cardiovascular function may make it possible to selectively interfere with the damage obesity inflicts on cardiovascular function.
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2019 — 2021 |
Huang, Chou-Long [⬀] Rahmouni, Kamal |
T32Activity Code Description: To enable institutions to make National Research Service Awards to individuals selected by them for predoctoral and postdoctoral research training in specified shortage areas. |
Iowa Training Program in Kidney and Hypertension Research
Abstract This application proposes continued funding for an interdisciplinary Iowa Training Program in Kidney and Hypertension research. The program provides research training for adult and pediatric nephrology fellows as well as PhD scientists interested in kidney and hypertension research in the University of Iowa, Carver College of Medicine. The primary purpose of the program is to provide intensive rigorous training for clinicians and scientists in broad ranges of areas related to kidney biology and disease and hypertension to transform this knowledge into improvements in patient care. The training program has been continuously funded for the past 25 years. The applicant pool is robust, and the program has filled consistently. The graduates from the program have published important contributions to biomedical research, and many have obtained faculty positions and received external funding for their research. The program faculty comprises 41 physician- scientists and basic scientists from 11 Departments with expertise in a broad range of scientific disciplines that are relevant to the kidney and hypertension. The training program research portfolio is organized into five themes based on and integrated with the existing strengths of research on campus: ion transport physiology and cell biology, renal genetics, hypertension, diabetes and renal metabolic diseases, and clinical and translation research in kidney diseases. The training curriculum includes mentored research training, didactic courses that include optional elective graduate-level courses, grant-writing workshop, and required courses in ethics and the responsible conduct of research, and attendance to journal clubs, works-in-progress and research seminar series. Specific training opportunities for patient-oriented research consist of a certification program in patient-oriented research and a Master or PhD degree in Translational Medicine.
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