Neuronal Protein Tyrosine Phosphatases in Metabolism

代谢中的神经蛋白酪氨酸磷酸酶

基本信息

批准号：
8105278
负责人：
Kendra Bence
金额：
$ 34.11万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8105278
关键词：
Action Potentials Acute Address Adipocytes Affect Biochemical Body Weight Brain Cations Comorbidity Development Diet Eating Energy Metabolism Fatty Liver Fatty acid glycerol esters Food Energy Frequencies Gene Expression Genetic Glucose Health Hormones Hypersensitivity Hypothalamic structure In Vitro Insulin Ion Channel Knock-out Knockout Mice Lead Leptin Leptin resistance Mediating Membrane Potentials Metabolic Metabolic Pathway Metabolism Mitotic Modeling Mus Neural Pathways Neuraxis Neurons Neuropeptide Gene Non-Insulin-Dependent Diabetes Mellitus Obesity Obesity associated disease Output PTPN11 gene Pathway interactions Peripheral Physiological Preparation Prevalence Property Prosencephalon Protein Tyrosine Phosphatase Regulation Reporter Rest Role Signal Pathway Signal Transduction Signaling Protein Site Slice Techniques Testing Therapeutic Tyrosine Phosphorylation blood glucose regulation cytokine design early onset energy balance glucose tolerance improved in vivo insulin sensitivity leptin receptor mouse model protein tyrosine phosphatase 1B recombinase research study response

项目摘要

DESCRIPTION (provided by applicant): The increasing prevalence of obesity and co-morbidities such as type II diabetes poses a significant health problem worldwide. Understanding the cellular signaling pathways underlying these pathological states is critical to assist in developing potential therapeutic treatment of these conditions. Leptin is a hormone secreted by fat, which acts on neurons in the central nervous system (CNS) to regulate food intake and energy expenditure. Leptin initiates an intracellular signaling cascade which in turn leads to changes in ion channel activity and gene expression that ultimately keep energy balance in check. The leptin signaling pathway is tightly controlled by tyrosine phosphorylation, and two protein tyrosine phosphatases (PTPs) have recently been implicated in regulation of the leptin signaling pathway in the brain: PTP1B and SHP2. These PTPs clearly have important in vivo roles in regulating energy balance, but the precise neuronal site(s) of action and the mechanism of PTP1B/SHP2 action at a cellular level are unknown. POMC and AgRP neurons in the hypothalamus are an important site of both energy balance and glucose homeostasis regulation. We hypothesize that PTP1B and SHP2 have important metabolic roles specifically in these neurons via either leptin-dependent or - independent effects. Our specific aims will address the effects of PTP1B or SHP2 deletion specifically in POMC- or AgRP-expressing neurons of mice on body weight, adiposity, leptin sensitivity, and glucose tolerance. Furthermore, these studies will address how PTP1B or SHP2 deletion in hypothalamic neurons affects the electrophysiological properties of these neurons. This combination of genetic, biochemical, and electrophysiological techniques will provide essential information about the cellular mechanism of PTP action in hypothalamic neurons as relates to energy balance. PUBLIC HEALTH RELEVANCE: Obesity and associated diseases such as type II diabetes are increasing at an alarming rate throughout the world. These proposed experiments will investigate the cellular mechanisms contributing to the development of leptin resistance, a pathological state which can lead to obesity and type II diabetes. We hypothesize that regulation of signaling by protein tyrosine phosphatases in the hypothalamus is an important component of the cellular signaling pathways regulating neuronal control of energy balance.

描述（由申请人提供）：肥胖症和合并症（例如II型糖尿病）的患病率不断增加，在全球范围内构成了重大健康问题。了解这些病理状态的基础的细胞信号通路对于有助于开发对这些疾病的潜在治疗治疗至关重要。瘦素是脂肪分泌的激素，该激素作用于中枢神经系统（CNS）中的神经元，以调节食物摄入和能量消耗。瘦素启动细胞内信号传导级联反过来，进而导致离子通道活性和基因表达的变化，最终使能量平衡受到控制。瘦素信号通路受酪氨酸磷酸化紧密控制，并且两种蛋白酪氨酸磷酸酶（PTP）最近与大脑中瘦素信号通路的调节有关：PTP1B和SHP2。这些PTP显然在调节能量平衡方面具有重要的体内作用，但是在细胞水平上的作用的精确神经元位点和PTP1B/SHP2作用的机制尚不清楚。下丘脑中的POMC和AGRP神经元是能量平衡和葡萄糖稳态调节的重要部位。我们假设PTP1B和SHP2通过瘦素依赖性或独立效应在这些神经元中具有重要的代谢作用。我们的具体目的将解决PTP1B或SHP2缺失的影响，专门针对小鼠表达POMC或AGRP神经元对体重，肥胖，瘦素敏感性和葡萄糖耐受性的影响。此外，这些研究将解决下丘脑神经元中的PTP1B或SHP2缺失如何影响这些神经元的电生理特性。遗传，生化和电生理技术的这种组合将提供有关下丘脑神经元中PTP作用的细胞机制的基本信息，这与能量平衡有关。公共卫生相关性：肥胖和相关疾病（例如II型糖尿病）在全球范围内以惊人的速度增加。这些提出的实验将研究导致瘦素耐药性发展的细胞机制，这是一种病理状态，可以导致肥胖症和II型糖尿病。我们假设下丘脑中蛋白酪氨酸磷酸酶对信号的调节是调节能量平衡神经元控制的细胞信号通路的重要组成部分。