Cell Growth Signaling in Cancer Development

描述（由申请人提供）：mTOR通路是一种信号传导系统，可响应生物体的营养状态调节生长和代谢。越来越多的证据表明，该途径通常在癌症，神经退行性疾病和糖尿病中失调，并且在衰老过程中也起着重要作用。大的mTOR蛋白激酶是药物雷帕霉素的靶点，也是两种多蛋白复合物mTOR复合物1（mTORC 1）和2（mTORC 2）的催化亚基，它们使mTOR通路的不同分支成核并响应不同的上游信号。mTORC 1响应于多种刺激，如生长因子、营养素和应激，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以及自噬。最近，我们发现mTORC 1以非细胞自主的方式调节肠干细胞（ISCs）对热量限制（CR）的自我更新。mTORC 1在潘氏细胞中起作用，潘氏细胞构成了ISC的生态位，位于肠隐窝的底部。CR是在没有营养不良的情况下减少热量限制， 小鼠，如减少肿瘤生长和增加寿命。哺乳动物中CR功能的机制尚不清楚。我们工作的广泛目标是从机制上理解mTORC 1如何感知Paneth细胞中的CR状态，其活性如何调节Paneth细胞功能以调节ISCs，并确定我们的工作对理解CR对肿瘤发生的影响的意义。 我们提出的工作的具体目标是：确定mTORC 1依赖性效应，通过CR在潘氏细胞中起作用，以促进ISC自我更新（目标1）;确定潘氏细胞用于调节肠道ISC更新的因素，以响应CR（目标2）;并确定潘氏细胞中CR和mTORC 1活性如何调节肠道肿瘤发生（目标3）。我们将通过生物化学、分子生物学和小鼠工程学的多学科方法来实现我们的目标。我们的研究结果可能对我们理解临床上重要的mTOR通路产生重要影响。此外，我们发现的信号传导机制可能在未来作为模拟CR的一些有益作用的治疗方法的发展目标。

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.