Bardet-Biedl Syndrome (BBS) is a genetically heterogeneous, pleiotropic disorder with clinical featuresthat include obesity and hypertension. There has been significant interest in identification of genescausing BBS and the elucidation of the pathophysiological mechanisms resulting in the clinical features ofthis syndrome due to the fact that components of the phenotype including obesity and hypertension arecommon causes of morbidity and mortality in human populations. Our group has independently identifiedseven of the eleven known BBS genes: BBS1, BBS2, BBS3, BBS4, BBS6, BBS9 and BBS11. Althougheleven BBS genes have been identified, elucidation of BBS gene function by sequence homology to othergenes with known function has proven elusive. We recently developed three different BBS mouse modelsby knocking out the Bbs2, Bbs4 and Bbs6 genes and demonstrated that all three models develop obesity,and that Bbs4 and Bbs6 knockout mice also have elevated arterial pressure compared to controls. Theincreased body mass in the knockout mice is associated with hyperleptinemia and leptin resistance, andthe mice with hypertension exhibit an increase in renal sympathetic activity. Building upon this strongpreliminary data, the aims of this proposal are directed at uncovering the pathophysiological mechanismsinvolved in obesity and high arterial blood pressure in BBS. Based on the preliminary data, wehypothesize that Central neurogenic mechanisms play a major pathophysiological role in obesity andhypertension associated with deletion of BBS genes in mice. The proposed experiments are aimed at: (1)Investigating the pathophysiological mechanisms leading to obesity in Bbs2, Bbs4 and Bbs6 knockoutmice with particular focus on the role of leptin resistance and potential defects in the hypothalamicnetwork controlling energy homeostasis. (2) Investigating the mechanisms of hypertension observed inthe Bbs4 and Bbs6 knockout mice by assessing the hemodynamic, sympathetic and hormonal systemsinvolved in blood pressure regulation; and (3) Use Bbs4 conditional knockout mice to determine whetherthe obesity and hypertension components of the BBS phenotype result primarily from loss of function ofthe gene in the central nervous system. The overall goal of the project is to uncover novel components ofblood pressure and body mass regulation, and to gain insight into pathophysiological mechanisms leadingto complex disorders.
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