Mechanisms of Leptin Resistance

描述（由申请人提供）： 瘦素是由脂肪细胞分泌的激素，其在控制体重的负反馈回路中充当主要信号。瘦素缺乏（ob/ob）小鼠和人类的瘦素治疗可导致体重大幅减轻，但更常见的饮食诱导的肥胖与高血浆瘦素水平和对瘦素减肥作用的抵抗有关。负责瘦素抵抗发展的分子和信号通路在很大程度上是未知的，但这些分子将是肥胖治疗的有吸引力的靶点。本申请描述了将阐明导致瘦素抗性的生理事件并鉴定代表瘦素敏感性的新型细胞调节剂的候选物的实验。这些实验利用了新的方法和模型，克服了阻碍研究瘦素抵抗的关键技术挑战之一：难以接近瘦素的直接靶细胞，即分散在下丘脑中的一小部分神经元。最后，候选瘦素调节剂的生理功能将探讨在啮齿动物模型的肥胖，使用遗传学，解剖学和药理学的方法相结合。将特别强调通过合成化学获得的小分子药物的使用，以快速验证体内候选药物。这项研究计划将有助于推进我的职业目标，领导一个应用我在合成化学和小分子发现方面的背景来解决肥胖和代谢疾病问题的国际研究实验室。这项研究的指导阶段将在洛克菲勒大学的杰弗里·弗里德曼的实验室进行，他一直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。这项研究旨在了解控制体重的基本机制，并确定肥胖治疗的新药物靶点。

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.