Mechanisms of Leptin Resistance

瘦素抵抗机制

基本信息

批准号：
7642800
负责人：
Zachary A. Knight
金额：
$ 8.96万
依托单位：
ROCKEFELLER UNIVERSITY
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：
2009-04-05 至 2011-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7642800
关键词：
Address Adipocytes Adipose tissue Adult Animal Model Animals Body Weight Body Weight decreased Body fat Cell Line Cells Chronic Complex Development Diet Dietary Fats Drug Delivery Systems Eating Environment Epitopes Event Fatty acid glycerol esters Feedback Gene Expression Gene Expression Profiling Genes Genetic Goals Hormones Human Hypothalamic structure Laboratories Laboratory Research Lead Leptin Leptin resistance Literature Measures Mentors Messenger RNA Metabolic Metabolic Diseases Modeling Molecular Mus Neurons Obese Mice Obesity Pathway interactions Pharmaceutical Preparations Phase Physiological Physiology Plasma Principal Investigator Public Health RNA Interference Reporting Research Resistance Resistance development Ribosomes Rodent Model Role Signal Pathway Signal Transduction Signaling Molecule Signaling Pathway Gene Study models Synthesis Chemistry Testing Transgenic Mice Universities Weight base career diabetes risk feeding fly hypertensive heart disease in vivo mouse model new technology new therapeutic target novel novel strategies obesity treatment promoter public health relevance research study response small molecule therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Leptin is a hormone secreted by adipocytes that acts as the major signal in a negative feedback loop controlling bodyweight. Leptin treatment of leptin deficient (ob/ob) mice and humans results in profound weight loss, but more common diet-induced obesity is associated with high plasma leptin levels and resistance to leptin's weight-reducing effects. The molecules and signaling pathways that are responsible for the development of leptin resistance are largely unknown, but such molecules would be attractive targets for obesity therapy. This application describes experiments that will clarify the physiological events that lead to leptin resistance and identify candidates that represent novel cellular regulators of leptin sensitivity. These experiments make use of new approaches and models that overcome one of the key technical challenges that has frustrated efforts to study leptin resistance: the difficulty of accessing leptin's direct target cells, a small subset of neurons dispersed throughout the hypothalamus. Finally, the physiological function of candidate leptin regulators will be explored in rodent models of obesity, using a combination of genetic, anatomical, and pharmacological approaches. Special emphasis will be placed on the use of small molecule drugs, accessed through synthetic chemistry, to rapidly validate candidates in vivo. This research plan will help advance my career goal to lead an interdisplinary research laboratory that applies my background in synthetic chemistry and small molecule discovery to address questions in obesity and metabolic disease. The mentored phase of this research will be conducted in the laboratory of Jeffrey Friedman at Rockefeller University, who has been a leader in field of molecular obesity research. PUBLIC HEALTH RELEVANCE: Obesity is a major public heath problem. This research seeks to understand basic mechanisms that control body weight and identify novel drug targets for obesity therapy.

描述（由申请人提供）：瘦素是一种由脂肪细胞分泌的激素，在控制体重的负反馈环中充当主要信号。瘦素治疗瘦素缺乏症（OB/OB）小鼠和人类的体重减轻，但更常见的饮食诱导的肥胖症与血浆瘦素水平高有关，并且对瘦素减轻体重减轻作用的耐药性。负责瘦素耐药性发展的分子和信号通路在很大程度上是未知的，但是这种分子将是肥胖治疗的有吸引力的靶标。该应用描述了将阐明导致瘦素耐药性的生理事件的实验，并确定代表瘦素敏感性的新细胞调节剂的候选者。这些实验利用了新的方法和模型克服了挫败研究瘦素耐药性努力的主要技术挑战之一：访问瘦素直接靶细胞的困难，这是整个下丘脑中分散的一小部分神经元的子集。最后，使用遗传，解剖和药理方法的组合，将在肥胖模型中探索候选瘦素调节剂的生理功能。通过合成化学访问的小分子药物的使用将特别重点放在体内迅速验证候选者的情况下。该研究计划将有助于促进我的职业目标，以领导跨跨性研究实验室，该实验室应用我的合成化学和小分子发现背景来解决肥胖和代谢疾病中的问题。这项研究的指导阶段将在洛克菲勒大学的杰弗里·弗里德曼（Jeffrey Friedman）实验室进行，他曾是分子肥胖研究领域的领导者。公共卫生相关性：肥胖是一个主要的公共卫生问题。这项研究试图了解控制体重的基本机制，并确定肥胖治疗的新药物靶标。