Cell Growth Signaling in Cancer Development

描述(申请人提供)：mTOR途径是一个信号系统，调节生长和新陈代谢，以响应有机体的营养状态。越来越多的证据表明，该途径在癌症、神经退行性疾病和糖尿病中普遍处于失控状态，在衰老过程中也发挥着重要作用。大的mTOR蛋白激酶是雷帕霉素药物的靶标，也是两个多蛋白复合体mTOR复合体1(MTORC1)和mTORC2(MTORC2)的催化亚单位，这两个复合体形成mTOR途径的不同分支，并对不同的上游信号做出反应。MTORC1对一系列不同的刺激做出反应，如生长因子、营养物质和压力，并调节许多合成代谢和分解代谢过程，包括蛋白质和脂肪合成以及自噬。最近，我们发现mTORC1以一种非细胞自主的方式调节肠道干细胞(ISCs)对热量限制(CR)的自我更新。MTORC1在Paneth细胞中起作用，Paneth细胞是ISCs的小生境，位于肠腺的底部。CR是在没有营养不良的情况下减少卡路里限制，对 例如，减少肿瘤生长和延长寿命。在哺乳动物中，CR功能的机制还不是很清楚。我们工作的广泛目标是从机制上理解mTORC1如何在Paneth细胞中感知CR状态，它的活动如何调节Paneth细胞的功能来调节ISCs，并确定我们的工作对理解CR对肿瘤发生的影响的意义。我们拟议工作的具体目标是：确定依赖mTORC1的效应器，通过这些效应，CR在Paneth细胞中作用于促进ISC自我更新(目标1)；确定Paneth细胞用来调节肠道ISC更新的因素(目标2)；以及确定Paneth细胞中的CR和mTORC1活性如何调节肠道肿瘤的发生(目标3)。我们将通过使用生物化学、分子生物学和鼠标工程工具的多学科方法来实现我们的目标。我们的结果可能会对我们理解临床上重要的mTOR通路产生重要的影响。此外，我们发现的信号机制在未来可能成为模仿CR的一些有益效果的治疗方法开发的目标。

DESCRIPTION (provided by applicant): The mTOR pathway is a signaling system that regulates growth and metabolism in response to the nutritional state of the organism. Increasing evidence indicates that the pathway is commonly deregulated in cancer, neurodegeneration, and diabetes, and also plays a major role in the aging process. The large mTOR protein kinase is the target of the drug rapamycin and the catalytic subunit of two multi-protein complexes, mTOR Complex 1 (mTORC1) and 2 (mTORC2) that nucleate distinct branches of the mTOR pathway and respond to different upstream signals. mTORC1 responds to a diverse set of stimuli, such as growth factors, nutrients, and stresses, and regulates many anabolic and catabolic processes, including protein and lipid synthesis and autophagy. Recently, we discovered that mTORC1 regulates, in a non-cell autonomous fashion, the self-renewal of intestinal stem cells (ISCs) in response to caloric restriction (CR). mTORC1 acts in Paneth cells, which constitute the niche for ISCs and are located at the base of intestinal crypts. CR is a reduction in caloric restriction in the absence of malnutrition and has very interesting effects in mice, such as decreasing tumor growth and increasing lifespan. The mechanisms through which CR functions are not well understood in mammals. The broad goals of our work are to arrive at a mechanistic understanding of how mTORC1 senses the CR state in Paneth cells, how its activity modulates Paneth cell function to regulate ISCs, and to determine the implications of our work for understanding the effects of CR on tumorigenesis. The specific aims of our proposed work are to: identify the mTORC1-dependent effectors through which CR acts in Paneth cells to promote ISC self renewal (Aim 1); determine the factors Paneth cells use to modulate intestinal ISC renewal in response to CR (Aim 2); and determine how CR and mTORC1 activity in Paneth cells regulate intestinal tumorigenesis (Aim 3). We will accomplish our goals with a multi- disciplinary approach that uses the tools of biochemistry, molecular biology, and mouse engineering. Our results are likely to have important consequences for our understanding of the clinically important mTOR pathway. Moreover, the signaling mechanisms we uncover may serve in the future as targets for the development of therapies that mimic some of the beneficial effects of CR.