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、异质性人类疾病 由包括早发性肥胖、高血压和心血管疾病在内的多效性表型引起。 尽管BBS是一种罕见的孟德尔疾病，但确定表型的潜在机制 与这种综合征相关的研究已经引起了极大的兴趣，因为 论坛中的肥胖和高血压等表型可能为理解普通人类提供线索 肥胖和高血压。我们使用一系列新的老鼠模型获得的初步数据 表型人类BBS指出神经发生机制对新陈代谢和 与BBS相关的心血管失调。事实上，我们发现了一种内源性的下丘脑瘦素 抵抗力是论坛中能量失衡和肥胖的主要原因。我们的数据还表明，神经 BBS基因缺失导致高血压的主要病理生理机制 老鼠身上的基因。最近，我们发现中枢神经系统BBSL基因的缺失(使用一种新的条件 BBSL FLOX/FLOX小鼠模型)概括了与BBS相关的肥胖表型，强调了 BBS基因在中枢神经系统能量平衡中的重要性。此外，BBS缺乏症 导致内质网应激缺陷和大脑中肾素-血管紧张素系统的激活。基于这些 结果，我们假设中枢神经系统中的BBS基因对能量平衡至关重要 以及动脉血压的自主调节。我们计划通过以下方式测试我们的中心假设 以下3个假设：1)神经元BBS蛋白对代谢和心血管起重要作用 在特定的神经元群体中，BBSL基因的调节和破坏改变了能量平衡， 自主神经功能和动脉压；2)脑血糖体缺陷，受体运输，内质网应激， 脑肾素-血管紧张素系统在代谢、自主神经和动脉系统中起着至关重要的作用。 与BBS相关的压力改变；以及3)BBS基因单倍体不足增加易感性 肥胖、自主神经功能障碍和高血压。 相关性(请参阅说明)： 这些研究具有重要意义，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下的新陈代谢和 中枢神经系统中BBS基因的心血管功能。从以下方面获得的新信息 这些研究将对肥胖和相关疾病的管理产生潜在的影响。 BBS中的心血管疾病以及常见的人类肥胖。

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.