The TSC-mTOR pathway in cellular and organismal energy metabolism

描述（由申请方提供）：哺乳动物雷帕霉素靶蛋白（mTOR）是一种中枢生长控制因子。最近的研究已经阐明了一个保守的信号通路，由TSC 1/TSC 2-Rheb-mTOR组成。TSC 1和TSC 2是结节性硬化症中突变的两个肿瘤抑制基因。TSC 1/TSC 2复合物作为GT3活化蛋白（GAP）发挥功能以抑制Rheb小GT3，其是mTOR的有效活化剂。该信号通路整合了广泛的细胞外和细胞内信号以调节细胞生长。mTOR活性通过细胞能量和氨基酸的可用性快速且显著地调节。先前的研究已经确定，TSC-mTOR通路在细胞水平上在细胞生长和营养可用性之间的协调中起着关键作用。本研究的主要目的是研究TSC-Rheb-mTOR通路在机体能量平衡中的作用，并阐明该通路在调节瘦素信号、食欲控制和能量消耗中的作用机制。我们将使用小鼠遗传学和细胞生物学技术来实现这些目标。本提案的具体目标是：目标1。目的2.明确POMC神经元中TSC 1在食欲、代谢控制和肥胖中的作用。目的：探讨TSC 1在AGRP/NPY神经元中对食欲的调节作用。阐明mTOR激活在诱导瘦素抵抗和摄食过多中的作用机制。确定低mTOR活性对食物摄入、代谢、肥胖、瘦素敏感性和抵抗高脂饮食诱导的肥胖的影响。TSC-mTOR通路在调节细胞生长的激素和营养信号中起着重要作用。本研究将探讨TSC-mTOR在影响瘦素信号传导和食欲控制中的作用。该项目产生的信息将为食欲调节、肥胖和糖尿病提供新的见解。

DESCRIPTION (provided by applicant): The mammalian target of rapamycin (mTOR) is a central growth controller. Recent studies have elucidated a conserved signaling pathway consisting of TSC1/TSC2-Rheb-mTOR. TSC1 and TSC2 are two tumor suppressor genes mutated in the tuberous sclerosis. The TSC1/TSC2 complex functions as a GTPase activating protein (GAP) to inhibit the Rheb small GTPase, which is a potent activator of mTOR. This signaling pathway integrates a wide range of extracellular and intracellular signals to regulate cell growth. mTOR activity is rapidly and dramatically regulated by the availability of cellular energy and amino acids. Previous studies have established that the TSC-mTOR pathway plays a critical role in the coordination between cell growth and nutrient availability at the cellular level. The major focus of this proposal is to investigate the function of TSC- Rheb-mTOR pathway in organismal energy balance and to elucidate the mechanism of this pathway in regulation of leptin signaling, appetite control, and energy expenditure. We will use mouse genetics and cell biological techniques to achieve these goals. The specific aims for this proposal are: Aim 1. To determine the function of TSC1 in POMC neurons in appetite and metabolic control and obesity Aim 2. To determine the function of TSC1 in AGRP/NPY neurons in regulation of appetite Aim 3. To elucidate the mechanism of mTOR activation in inducing leptin resistance and hyperphagia Aim 4. To determine the effect of low mTOR activity on food intake, metabolism, obesity, leptin sensitivity, and resistant to high fat diet-induced obesity. PUBLIC HEALTH RELEVANCE The TSC-mTOR pathway plays a major role in hormonal and nutritional signals to regulate cell growth. This proposal will investigate the function of TSC-mTOR in affecting leptin signaling and appetite control. The information generated from this project will provide new insights into to appetite regulation, obesity, and diabetes.