Cell Growth Signaling in Cancer Development

癌症发展中的细胞生长信号传导

• 批准号: 8997438
• 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 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8997438
• 关键词: Aging-Related Process; Autophagocytosis; Caloric Restriction; Catabolic Process; Catalytic Domain; Cell physiology; Cells; Coculture Techniques; Communities; Complex; Development; Diabetes Mellitus; Drug Targeting; Energy Intake; Engineering; FRAP1 gene; Future; Goals; Grant; Growth; 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; dietary manipulation; 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，神经退行性变性和糖尿病中受管制，并且在衰老过程中也起着重要作用。大型MTOR蛋白激酶是药物雷帕霉素的靶标和两个多蛋白质复合物的催化亚基MTOR复合物1（MTORC1）和2（MTORC2），它们对MTOR途径的不同分支有核并响应不同的上游信号。 MTORC1对各种刺激的反应，例如生长因子，营养素和应力，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以非电池自主的方式调节肠道干细胞（ISC）对热量限制（CR）的自我更新。 MTORC1作用于Paneth细胞，该细胞构成ISC的利基市场，位于肠道隐窝的底部。 CR是在没有营养不良的情况下降低热量限制的，并且对 小鼠，例如减少肿瘤生长和寿命增加。哺乳动物中CR功能的机制尚未得到很好的了解。我们工作的广泛目标是对MTORC1在Paneth细胞中如何感知CR状态的机械理解，其活性如何调节Paneth细胞功能调节ISC，并确定我们工作对了解CR对肿瘤造成影响的影响的含义。 我们提出的工作的具体目的是：确定CR在Paneth细胞中作用以促进ISC自我更新的MTORC1依赖性效应子（AIM 1）；确定Paneth细胞用来调节CR的肠道ISC更新的因素（AIM 2）；并确定Paneth细胞中的Cr和MTORC1活性如何调节肠道肿瘤发生（AIM 3）。我们将通过多学科方法来实现我们的目标，该方法使用生物化学，分子生物学和小鼠工程的工具。我们的结果可能会对我们对临床上重要的MTOR途径的理解产生重要影响。此外，我们发现的信号传导机制可能会在未来作为模仿CR的某些有益作用的疗法的靶标。