Mammalian Target of Rapamycin (mTOR) signaling in health and longetivity

描述（由申请方提供）：哺乳动物雷帕霉素靶蛋白（mTOR）信号通路调节生长和代谢，以响应营养素的可用性。mTOR途径是高度保守的，并且在大多数真核生物中发现了该途径的中心组分mTOR蛋白激酶的同源物，包括酵母、蠕虫、苍蝇、植物、小鼠和人类。mTOR是两种不同复合物mTORd和mTORC 2的成员，每种复合物调节不同的细胞靶点。最近的研究表明，抑制TOR信号可以延长酵母、蠕虫和苍蝇的寿命。然而，这种效应背后的机制尚不清楚，目前还不清楚mTOR信号转导的减少是否会促进哺乳动物的长寿。人们提出抑制mTOR信号传导可以模拟卡路里限制的作用，这是一种促进许多生物体健康和长寿的干预措施，因此可能在治疗糖尿病、神经退行性疾病和其他与年龄相关的疾病方面具有治疗价值。在这份提案中，我概述了我将进行的研究，以更好地了解mTOR信号减少对哺乳动物健康和衰老的影响。我将在组织培养模型中使用来自mTOR、Raptor（mTORCI的一个组成部分）和Rictor（mTORC2的一个组成部分）杂合敲除小鼠的小鼠胚胎成纤维细胞来检查应激抗性，这通常与寿命相关。使用mTOR、Raptor或Rictor杂合子小鼠，我将研究mTORCI和mTORC2信号传导在抗应激和衰老中的作用。将允许这些杂合敲除小鼠的群体变老，并将评估长寿的生物标志物，包括胰岛素水平和葡萄糖耐量。标准RNA微阵列和蛋白质样本分析将用于分析mTORCI和mTORC2信号在衰老和长寿中的作用。最后，Raptor和Rictor的条件性组织特异性敲除将被检查其调节对高脂饮食的抗性的能力。抑制哺乳动物雷帕霉素靶蛋白（mTOR）信号传导可以延长低等生物的寿命，并且已经提出模拟热量限制的效果，这是一种促进哺乳动物健康和长寿的干预措施。因此，抑制mTOR信号传导可能在治疗糖尿病、癌症、神经变性和其他年龄相关疾病中具有治疗价值。该提案旨在确定抑制mTOR信号传导是否确实促进哺乳动物的健康和长寿，并确定这种效应背后的机制。

DESCRIPTION (provided by applicant): The mammalian target of rapamycin (mTOR) signaling pathway regulates growth and metabolism in response to the availability of nutrients. The mTOR pathway is highly conserved, and a homologue of the central component of the pathway, the mTOR protein kinase, is found in most eukaryotes, including yeast, worms, flies, plants, mice, and humans. mTOR is a member of two distinct complexes, mTORd and mTORC2, each of which regulates distinct cellular targets. Recent studies have demonstrated that inhibition of TOR signaling can extend the lifespan of yeast, worms, and flies. However, the mechanism behind this effect is unknown, and it is not yet known if decreased mTOR signaling will promote longevity in mammals. Inhibition of mTOR signaling has been proposed to mimic the effects of calorie restriction, an intervention which promotes health and longevity in many organisms, and may therefore be of therapeutic value in the treatment of diabetes, neurodegeneration and other age-related diseases. In this proposal, I outline studies that I will undertake to better understand the effects of decreased mTOR signaling on mammalian health and aging. I will examine stress resistance, which often correlates with longevity, in a tissue culture model using mouse embryonic fibroblasts derived from mTOR, Raptor (a component of mTORCI), and Rictor (a component of mTORC2) heterozygous knockout mice. Using mice heterozygous for mTOR, Raptor, or Rictor, I will examine the role of both mTORCI and mTORC2 signalling in stress resistance and aging. Populations of these heterozygous knockout mice will be allowed to age, and biomarkers of longevity, including insulin levels and glucose tolerance, will be assessed. Standard RNA microarrays and analysis of protein samples will be used to analyze the role of mTORCI and mTORC2 signaling in aging and longevity. Finally, conditional tissue specific knockouts of Raptor and Rictor will be examined for their ability to regulate resistance to a high-fat diet. Inhibition of the mammalian target of rapamycin (mTOR) signalling extends longevity in lower organisms, and has been proposed to mimic the effects of calorie restriction, an intervention that promotes health and longevity in mammals. Inhibition of mTOR signalling may therefore be of therapeutic value in the treatment of diabetes, cancer, neurodegeneration and other age-related diseases. This proposal seeks to determine if inhibition of mTOR signalling does promotes health and longevity in mammals, and to determine the mechanism behind this effect.