Cell Growth Signaling in Cancer Development

描述（由申请人提供）：mTOR通路是一种信号系统，根据生物体的营养状态调节生长和代谢。越来越多的证据表明，该通路在癌症、神经变性和糖尿病中普遍失调，并且在衰老过程中也起着重要作用。大mTOR蛋白激酶是药物雷帕霉素的靶标，也是两个多蛋白复合物mTOR复合物1 （mTORC1）和2 （mTORC2）的催化亚基，它们构成mTOR通路的不同分支，并对不同的上游信号作出反应。mTORC1响应多种刺激，如生长因子、营养物质和应激，并调节许多合成代谢和分解代谢过程，包括蛋白质和脂质合成和自噬。最近，我们发现mTORC1以非细胞自主的方式调节肠道干细胞（ISCs）的自我更新，以响应热量限制（CR）。mTORC1在Paneth细胞中起作用，Paneth细胞构成ISCs的生态位，位于肠隐窝的底部。CR是指在没有营养不良的情况下减少热量限制在

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.