Leptin Receptor Signaling and Regulation of Sympathetic and Cardiovascular Funct

瘦素受体信号传导以及交感神经和心血管功能的调节

• 批准号: 7249784
• 负责人: ALLYN L. MARK
• 金额: $ 56.05万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7249784
• 关键词: 1-Phosphatidylinositol 3-Kinase; Acute; Alleles; Angiotensins; Appetite Depressants; Attenuated; Biological Preservation; Body Weight; Body Weight decreased; Brain; Brown Fat; Cardiovascular Diseases; Cardiovascular system; Chronic; Collaborations; Data; Denervation; Desire for food; Development; Diet; Disruption; Down-Regulation; Energy Metabolism; Fatty acid glycerol esters; Gene Targeting; Genetic; Genetically Engineered Mouse; Hypertension; Hypothalamic structure; Infusion procedures; Interruption; Kidney; Lead; Leptin; Link; MAP Kinase Gene; Mediating; Mediator of activation protein; Methods; Microinjections; Mitogen-Activated Protein Kinases; Modeling; Molecular; Molecular Genetics; Morbidity - disease rate; Mus; Nerve; Obese Mice; Obesity; Pathway interactions; Phosphoinositide-3-Kinase, Catalytic, Gamma Polypeptide; Phosphotransferases; Physiological; Protein Overexpression; Receptor Signaling; Regulation; Research Personnel; Resistance; Role; STAT3 gene; Signal Pathway; Signal Transduction; Site; Structure of nucleus infundibularis hypothalami; Sympathetic Nervous System; Techniques; Testing; Thermogenesis; Thinking; Transfection; Transgenic Organisms; Viral; Virus; Weight; base; blood pressure regulation; inhibitor/antagonist; insight; leptin receptor; mortality; mouse model; neurophysiology; pressure; receptor; recombinase; research study; response; trafficking

Chronic administration of leptin increases arterial pressure through renal sympathetic activation. Renal denervation substantially attenuates obesity induced hypertension.The ability of leptin to increase renal sympathetic nerve activity (SNA)and arterial pressure is preserved in two murine models of obesity despite resistance to the appetite suppressant action of leptin suggesting that leptin could contribute to hypertension in obesity despite resistance to its appetite suppressant actions. The focus of this project is on the hypothalamic molecular leptin signaling pathways mediating selective leptin actions and specifically renal SNA and arterial pressure versus appetite suppressant responses. We have demonstrated that the renal SNA responses to leptin are mediated through PI3 kinase. In contrast, based on preliminary studies, we will test the hypothesis that hypothalamic STAT3 and MAP, while mediating appetite suppressant effectsof leptin, are not involved in leptin induced increases in renal SNA and arterial pressure. Thus, disrupting leptin induced STAT3 or MAP kinase signaling would attenuate the appetite suppressant actions of leptin while preserving the renal SNA and arterial pressure responses. Based on this hypothesis, resistance to the effects of leptin on STATS and MAPK signaling in obesity could promote obesity induced hypertension. We will combine two complementary approaches to evaluate the role of STATS and MAP kinase on renal SNA and arterial pressure responses to leptin: 1) study of obese mouse models with gene targeted disruption of Shp 2 that mediates leptin induced MAP kinase activation or of leptin STATS signaling; and 2) study of mice with conditional "floxed" alleles allowing site specific deletion of STATS, MAP kinase or the leptin receptor using targeted viral microinjections of Cre recombinase into the arcuate nucleus. A distinctive strength of this project is a constellation of highly interactive investigators who can assure the successful application of a combination of robust cardiovascular, neurophysiologic and genetic strategies to advance understanding of the role of leptin signaling pathways in regulation of renal SNA and arterial pressure. Insight into mechanisms of leptin actions on the sympathetic nervous system and arterial pressure should shed insight into cardiovascular complications of obesity.

长期服用瘦素可通过激活肾交感神经来增加动脉压。肾 去神经实质上减轻肥胖引起的高血压。瘦素增加肾脏的能力 交感神经活动(SNA)和动脉压在两种肥胖小鼠模型中保持不变 尽管瘦素抑制食欲的作用受到抵抗，但这表明瘦素可能有助于 高血压在肥胖中，尽管对其具有抑制食欲的作用。这个项目的重点是 下丘脑分子瘦素信号通路介导选择性瘦素作用的研究 具体地说，肾脏SNA和动脉压与食欲抑制反应。我们有 表明肾脏SNA对瘦素的反应是通过PI3激酶介导的。相比之下， 在初步研究的基础上，我们将检验下丘脑STAT3和MAP， 虽然瘦素有调节食欲抑制的作用，但不参与瘦素诱导的增加 肾SNA和动脉压。因此，干扰瘦素可诱导STAT3或MAP激酶 信号将减弱瘦素的食欲抑制作用，同时保护肾脏 SNA和动脉压反应。基于这一假设，对瘦素作用的抵抗 肥胖中的STATS和MAPK信号转导通路可促进肥胖性高血压。我们会 联合两种互补方法评估STATS和MAP激酶在肾脏SNA中的作用 和动脉血压对瘦素的反应：1)基因靶向干扰肥胖小鼠模型的研究 SHP-2介导瘦素诱导的MAP激酶激活或Leptin STATS信号转导；以及2)研究 携带条件性等位基因的小鼠，这些等位基因允许STATS、MAP激酶或瘦素的位点特异性缺失 使用靶向病毒微注射Cre重组酶到弓状核的受体。一种与众不同的 这个项目的优势是一群高度互动的调查人员，他们可以确保成功 应用强大的心血管、神经生理学和遗传策略的组合来推进 了解瘦素信号通路在调节肾脏SNA和动脉压中的作用。 深入了解瘦素对交感神经系统和动脉压的作用机制 深入了解肥胖引起的心血管并发症。