The TSC-mTOR pathway in cellular and organismal energy metabolism

描述(申请人提供)：雷帕霉素(MTOR)的哺乳动物靶标是一种中枢生长控制因子。最近的研究阐明了由TSC1/TSC2-Rheb-mTOR组成的一条保守的信号通路。TSC1和TSC2是结节性硬化症中突变的两个抑癌基因。TSC1/TSC2复合体作为GTP酶激活蛋白(GAP)抑制rheb小GTP酶，后者是mTOR的有效激活剂。这个信号通路整合了广泛的细胞外和细胞内信号来调节细胞生长。MTOR活性受细胞能量和氨基酸的可获得性快速而显著地调节。以往的研究已经证实，TSC-mTOR途径在细胞水平上协调细胞生长和养分供应方面发挥着关键作用。本研究的重点是研究TSC-Rheb-mTOR通路在机体能量平衡中的作用，并阐明该通路在瘦素信号、食欲控制和能量消耗中的调节机制。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。本研究的具体目的是：1.确定POMC神经元中TSC1在食欲、代谢控制和肥胖中的功能；2.确定AGRP/NPY神经元中TSC1在食欲调节中的功能；3.阐明mTOR激活在诱导瘦素抵抗和过度吞噬中的作用机制；4.确定mTOR活性降低对食物摄取、代谢、肥胖、瘦素敏感性和抵抗高脂饮食诱导的肥胖的影响。公共卫生相关性TSC-mTOR途径在调节细胞生长的激素和营养信号中发挥重要作用。这项建议将研究TSC-mTOR在影响瘦素信号和食欲控制方面的功能。这个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.