Functions of the Nuclear Receptor SHP

核受体 SHP 的功能

• 批准号: 7210533
• 负责人: DAVID D MOORE
• 金额: $ 44.13万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7210533
• 关键词: Accounting; Acute; Address; Aldosterone; Animals; Automobile Driving; Bile Acid Biosynthesis Pathway; Bile Acids; Binding; Blood Pressure; Brain natriuretic peptide; Brown Fat; Diabetes Mellitus; Diet; Disease; Dyslipidemias; Epidemic; Exhibits; Feedback; Gene Targeting; Genes; Goals; Heart Atrium; Hepatic; Homeostasis; Hypertension; Knock-out; Knockout Mice; Laboratories; Metabolic; Metabolic Diseases; Metabolic syndrome; Modeling; Molecular; Mus; Nuclear Hormone Receptors; Nuclear Receptors; Numbers; Obesity; Orphan; Pathway interactions; Phenotype; Physiological; Production; Regulation; Regulator Genes; Renin; Resistance; Role; Stress; Syndrome; Tissues; Transgenic Model; Transgenic Organisms; Triglycerides; base; gain of function; glucose metabolism; insight; insulin sensitivity; insulin sensitivity/resistance; mutant; novel strategies; receptor

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.

描述(申请人提供)：目前的肥胖流行正在推动代谢综合征(X综合征)的急剧增加，X综合征是一系列疾病，包括糖尿病、血脂异常和高血压。这一建议采用了广泛的方法来理解孤儿受体SHP在这种综合征的大部分(如果不是所有的主要方面)中的作用的分子机制。当受到适当的压力时，SHP基因缺失的小鼠表现出许多有趣的表型，包括胆汁酸生物合成的负反馈调节丧失，胆汁酸对肝甘油三酯合成的急性抑制作用丧失，对饮食诱导的肥胖的抵抗力，胰岛素敏感性增加，以及对醛固酮和肾素增加以及心房利钠和B型利钠肽基因表达减少的联合高血压效应的抵抗力。这项建议的总体目标是描述失去SHP的生理影响，并确定这些影响的分子基础。其具体目的是：1)建立合适的特定基因敲除和转基因功能模型，以便于研究SHP的组织特异性效应。2)确定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)确定SHP-/-小鼠胰岛素敏感性增加的生理基础，并确定这种作用的分子机制。4)鉴定SHP基因敲除中多个高血压通路活性增加的基础及其对这些通路影响的抵抗力。我们相信，确定SHP功能丧失的具体机制将为研究导致代谢稳态的连锁机制提供新的见解，并为解决代谢性疾病提供新的方法。