Role of Brain Bardet-Biedl Syndrome Genes in Metabolic and Cardiovas Regulation

Bardet-Biedl综合征（BBS）是一种常染色体、隐性遗传、异质性的人类疾病， 多效表型包括早发性肥胖、高血压和心血管疾病。 虽然BBS是一种罕见的孟德尔遗传疾病，但确定其表型的潜在机制 与这种综合征相关的疾病引起了极大的兴趣，因为 BBS中的肥胖和高血压等表型可能会为了解普通人类提供线索 肥胖和高血压。我们使用一系列新的小鼠模型获得的初步数据， 表型人类BBS指出了神经原性机制对代谢和 与BBS相关的心血管失调。事实上，我们发现了一种内在的下丘脑瘦素， 抵抗是BBS中能量失衡和肥胖的主要原因。我们的数据还表明， 机制在与Bbs缺失相关的高血压中起主要的病理生理作用 老鼠的基因最近，我们发现Bbsl基因的CNS缺失（使用新的条件性 Bbsl flox/flox小鼠模型）重现了与BBS相关的肥胖表型，突出了 Bbs基因在中枢神经系统能量稳态中的重要性。此外，BBS缺陷 导致ER应激缺陷和脑中肾素-血管紧张素系统的激活。基于这些 根据这些发现，我们假设中枢神经系统中的Bbs基因对能量稳态至关重要 以及动脉压的自主调节。我们计划通过追踪 以下3个假设：1）神经元BBS蛋白在代谢和心血管方面是重要的 在特定神经元群体中Bbs 1基因的调节和破坏改变了能量稳态， 自主神经功能和动脉压; 2）脑BBSome缺陷，受体运输，ER应激， 和脑的肾素-血管紧张素系统在代谢、自主神经和动脉 与BBS相关的压力改变;和3）Bbs基因的单倍不足增加易感性 肥胖、自主神经功能紊乱和高血压。 相关性（参见说明）： 这些研究意义重大，因为它们将为神经元Bbs的作用提供重要的见解， 基因，并确定新的基本机制的调节代谢和 中枢神经系统中的Bbs基因对心血管功能的影响。新的信息从 这些研究将对肥胖症的管理和相关的 BBS中的心血管疾病以及常见的人类肥胖症。

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.