SH2-B Regulation of Hypothalamic AgRP/NPY Neurons

SH2-B 对下丘脑 AgRP/NPY 神经元的调节

• 批准号: 7263859
• 负责人: David L Morris
• 金额: $ 3.31万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7263859
• 关键词: 1-Phosphatidylinositol 3-Kinase; ART protein; Address; Adipose tissue; Binding; Binding Proteins; Binding Sites; Biological; Body Weight; CARTPT gene; Cultured Cells; Cytoplasmic Tail; Desire for food; Development; Disruption; Eating; Energy Metabolism; Food Intake Regulation; Homeostasis; Hormonal; Hyperphagia; Hypothalamic structure; IRS2 gene; JAK2 gene; Knockout Mice; Laboratories; Leptin; Leptin resistance; Mediating; Mediator of activation protein; Metabolic; Mus; Neuraxis; Neurons; Neuropeptides; Obesity; Pathway interactions; Phenotype; Phosphoinositide-3-Kinase, Catalytic, Gamma Polypeptide; Phosphorylation; Phosphotransferases; Phosphotyrosine; Population; Pro-Opiomelanocortin; Protein Tyrosine Kinase; Recruitment Activity; Regulation; Relative (related person); Role; SH2B gene; Signal Transduction; Signaling Molecule; Structure of nucleus infundibularis hypothalami; Testing; Tyrosine; Tyrosine Phosphorylation; driving force; energy balance; human IRS2 protein; in vivo; increased appetite; insight; loss of function; neuropeptide Y; receptor; response

DESCRIPTION (provided by applicant): Leptin suppresses food intake via its biological actions on the central nervous system. SH2-B, a JAK2 binding protein, is expressed in leptin-sensitive neurons within the hypothalamus, and promotes leptin signaling in cultured cells. SH2-B deficient mice develop hyperphagia, leptin resistance, and obesity, confirming that SH2-B is a key mediator of leptin action and energy balance in vivo. This proposal will address the role of SH2-B in AgRP neurons, one population of leptin sensitive neurons in the hypothalamus implicated in the control of food intake. A conditional loss-of-function approach (Cre/LoxP) will be used to test the central hypothesis that SH2-B regulates energy balance predominantly by regulating leptin sensitivity in AgRP neurons within the arcuate nucleus of the hypothalamus. The extent to which SH2-B directly regulates leptin signaling in AgRP neurons will be determined (aim 1), and the relative contribution of SH2-B in AgRP neurons to the intrinsic regulation of energy balance and leptin sensitivity (aim 2) will be addressed. These studies will provide considerable insight into the mechanisms by which SH2-B promotes leptin sensitivity and contributes to the central regulation of energy homeostasis.

描述（由申请人提供）：瘦素通过其对中枢神经系统的生物作用抑制食物摄入。 SH2-B 是一种 JAK2 结合蛋白，在下丘脑内的瘦素敏感神经元中表达，并促进培养细胞中的瘦素信号传导。 SH2-B 缺陷小鼠出现食欲亢进、瘦素抵抗和肥胖，证实 SH2-B 是体内瘦素作用和能量平衡的关键介质。该提案将解决 SH2-B 在 AgRP 神经元中的作用，AgRP 神经元是下丘脑中与食物摄入控制有关的瘦素敏感神经元群。条件功能丧失方法 (Cre/LoxP) 将用于测试中心假设，即 SH2-B 主要通过调节下丘脑弓状核内 AgRP 神经元的瘦素敏感性来调节能量平衡。将确定 SH2-B 在 AgRP 神经元中直接调节瘦素信号传导的程度（目标 1），并将解决 AgRP 神经元中 SH2-B 对能量平衡和瘦素敏感性的内在调节的相对贡献（目标 2）。这些研究将为 SH2-B 促进瘦素敏感性并有助于能量稳态的中央调节的机制提供深入的见解。