Functions of the Nuclear Receptor SHP

描述（由申请人提供）：当前的肥胖流行正在导致代谢综合征（X综合征）的急剧增加，这是包括糖尿病、血脂异常和高血压在内的一系列疾病。该建议采用广泛的方法来理解孤儿受体SHP在大多数（如果不是全部）该综合征主要方面的影响的分子机制。当受到适当的应激时，SHP小鼠表现出许多有趣的表型，包括胆汁酸生物合成负反馈调节的丧失，胆汁酸对肝脏甘油三酯产生的急性抑制作用的丧失，对饮食诱导的肥胖的抵抗，胰岛素敏感性的增加，对醛固酮和肾素增加的联合高血压作用的抵抗，以及心房和b型利钠肽基因表达的减少。本提案的总体目标是表征SHP损失的生理影响，并确定这些影响的分子基础。具体目的是：1)建立合适的功能模型的特异性敲除和转基因增益，以促进SHP组织特异性效应的研究。2)表征棕色脂肪组织活性增加在SHP缺陷小鼠肥胖抵抗中的作用，并确定这种活性增加的分子基础。3)描述SHP-/-小鼠胰岛素敏感性增加的生理基础，并确定导致这种效应的分子机制。4)描述SHP敲除中多种高血压通路活性增加的基础及其对这些通路影响的抵抗。我们相信，确定影响SHP功能丧失的具体机制将为导致代谢稳态的联锁机制提供新的见解，并为解决代谢疾病提供新的方法。

DESCRIPTION (provided by applicant): The current obesity epidemic is driving a dramatic increase in the metabolic syndrome (syndrome X), a constellation of disorders that includes diabetes, dyslipidemias and hypertension. This proposal takes a broad approach to understanding the molecular mechanisms that account for effects of the orphan receptor SHP in most, if not all of the primary aspects of this syndrome. When subjected to appropriate stresses, SHP null mice exhibit a number of intriguing phenotypes including loss of negative feedback regulation of bile acid biosynthesis, loss of an acute inhibitory effect of bile acids on hepatic triglyceride production, resistance to diet induced obesity, increased insulin sensitivity, and resistance to the combined hypertensive effects of increased aldosterone and renin and decreased expression of the atrial and B-type natriuretic peptide genes. The overall goal of this proposal is to characterize the physiologic effects of the loss of SHP and define the molecular basis for these effects. The specific aims are to: 1) Generate appropriate specific knockout and transgenic gain of function models to facilitate studies of tissue specific effects of SHP. 2) Characterize the role of increased brown adipose tissue activity in the obesity resistance of the SHP deficient mice and define the molecular basis for this increased activity. 3) Characterize the physiologic basis for the increased insulin sensitivity of the SHP-/- mice and identify molecular mechanisms that contribute to this effect. 4) Characterize the basis for the increased activity of multiple hypertensive pathways in the SHP knockouts and their resistance to the effects of these pathways. We believe that identifying the specific mechanisms that account for the effects of the loss of SHP function will provide new insights into the interlocking mechanisms that result in metabolic homeostasis and new approaches to addressing metabolic diseases.