The TSC-mTOR pathway in cellular and organismal energy metabolism

描述（由申请人提供）：哺乳动物雷帕霉素靶点（mTOR）是一种中枢生长控制器。最近的研究已经阐明了一个由TSC1/TSC2-Rheb-mTOR组成的保守信号通路。TSC1和TSC2是结节性硬化症中发生突变的两个肿瘤抑制基因。TSC1/TSC2复合物作为GTPase激活蛋白（GAP）抑制Rheb小GTPase，后者是mTOR的有效激活剂。该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的活性受到细胞能量和氨基酸的迅速而显著的调节。先前的研究已经证实，TSC-mTOR通路在细胞水平上对细胞生长和营养可用性之间的协调起着关键作用。本课题主要研究TSC- Rheb-mTOR通路在机体能量平衡中的作用，阐明该通路调控瘦素信号、食欲控制和能量消耗的机制。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。本建议的具体目标是：目标1。目的：探讨POMC神经元中TSC1在食欲、代谢控制和肥胖中的作用。目的：探讨TSC1在AGRP/NPY神经元中调节食欲的作用。目的：阐明mTOR激活诱导瘦素抵抗和贪食的机制。确定低mTOR活性对食物摄入、代谢、肥胖、瘦素敏感性和对高脂饮食引起的肥胖的抵抗的影响。

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.