Cell Growth Signaling in Cancer Development

癌症发展中的细胞生长信号传导

• 批准号: 8833250
• 负责人: David M. Sabatini
• 金额: $ 40.26万
• 依托单位: WHITEHEAD INSTITUTE FOR BIOMEDICAL RES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-08 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8833250
• 关键词: Aging-Related Process; Autophagocytosis; Caloric Restriction; Catabolic Process; Catalytic Domain; Cell physiology; Cells; Coculture Techniques; Communities; Complex; Development; Diabetes Mellitus; Diet; Drug Targeting; Energy Intake; Engineering; Future; Goals; Grant; Growth; Growth Factor; Health; Intestines; Lipids; Longevity; Malignant Neoplasms; Malnutrition; Mammals; Mediating; Medical; Metabolism; Molecular; Molecular Biology; Mus; Nerve Degeneration; Nutrient; Nutritional; Organ; Organism; Organoids; Paneth Cells; Pathway interactions; Physiological; Physiological Processes; Physiology; Play; Process; Progress Reports; Protein Kinase; Proteins; Role; Signal Transduction; Sirolimus; Stem cells; Stimulus; Stress; Structure; System; Therapeutic; Tissues; Tumor Suppressor Proteins; Work; adult stem cell; base; biochemical tools; cell growth; cell type; human FRAP1 protein; human disease; in vivo; insight; interest; intestinal crypt; mTOR Inhibitor; mTOR protein; mouse model; notch protein; novel; protein complex; response; self-renewal; stem cell division; therapy development; tumor growth; tumorigenesis

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.

描述（由申请人提供）：mTOR 途径是一种信号系统，可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、神经退行性疾病和糖尿病中通常失调，并且在衰老过程中也发挥着重要作用。大 mTOR 蛋白激酶是药物雷帕霉素和两个多蛋白复合物 mTOR 复合物 1 (mTORC1) 和 2 (mTORC2) 的催化亚基的靶标，它们使 mTOR 通路的不同分支成核并对不同的上游信号做出反应。 mTORC1 对多种刺激做出反应，例如生长因子、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以及自噬。最近，我们发现 mTORC1 以非细胞自主方式调节肠干细胞 (ISC) 的自我更新以响应热量限制 (CR)。 mTORC1 在潘氏细胞中起作用，潘氏细胞构成了 ISC 的微环境，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，对以下方面有非常有趣的影响： 小鼠，例如减少肿瘤生长和延长寿命。 CR 在哺乳动物中发挥作用的机制尚不清楚。我们工作的总体目标是从机制上理解 mTORC1 如何感知潘氏细胞中的 CR 状态，其活性如何调节潘氏细胞功能以调节 ISC，并确定我们的工作对于理解 CR 对肿瘤发生。 我们提出的工作的具体目标是：确定 CR 在潘氏细胞中发挥作用以促进 ISC 自我更新的 mTORC1 依赖性效应器（目标 1）；确定潘氏细胞用于调节肠道 ISC 更新以响应 CR 的因素（目标 2）；并确定潘氏细胞中的 CR 和 mTORC1 活性如何调节肠道肿瘤发生（目标 3）。我们将通过使用生物化学、分子生物学和小鼠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 通路产生重要影响。此外，我们发现的信号传导机制可能在未来作为开发模仿 CR 的一些有益作用的疗法的目标。