Novel molecular targets within the TOR pathway

TOR 通路中的新分子靶点

基本信息

批准号：
8385394
负责人：
Daniel J Burke
金额：
$ 23.7万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8385394
关键词：
Aging Animal Model Autophagocytosis Biogenesis Biology Cell Cycle Cell physiology Cells Chemicals Collection Complex Coupled Data Essential Genes Genes Genetic Genetic Transcription Goals Growth Homologous Gene Human Intervention Knowledge Link Longevity Lower Organism Malignant Neoplasms Medical Methods Mission Modeling Molecular Molecular Target NIH Program Announcements Nutrient Organism Output Pathway interactions Pharmaceutical Chemistry Physiological Protein Kinase Proteins Public Health Research Ribosomes Role Saccharomyces cerevisiae Saccharomycetales Signal Pathway Signal Transduction Sirolimus Somatomedins System Time Tweens United States National Institutes of Health Yeasts biological adaptation to stress cell growth cell type chemical genetics detection of nutrient disability genetic profiling genome wide association study genome-wide human FRAP1 protein in vitro Assay inhibitor/antagonist innovation man member mutant novel tool

项目摘要

DESCRIPTION (provided by applicant): TOR (target of rapamycin) is evolutionarily conserved from yeast to humans and has a pivotal role of controlling cell growth in all cell types. There is fundamental gap in our understanding of the physiological pathways that interact with TOR and how modulating those pathways regulate lifespan and healthspan. There is an urgent need to identify the full spectrum of interactions that describes TOR activity. The long-term goal is to have a complete understanding of how TOR regulates cellular physiology. The immediate goal of this application is to use a systems approach and the budding yeast Saccharomyces cerevisiae to fill important gaps in our knowledge of TOR activity. It is the evolutionary conservation of the TOR complexes coupled with the outstanding genetic tools that are available for studying budding yeast that are central to this application. The central hypothesis i that there are physiological pathways that interact with TOR or are regulated by TOR that are unidentified and will be evolutionarily conserved from yeast to humans. The rationale is that novel pathways will be discovered using a new and under-utilized genetic approach called "complex haplo-insufficiency" (CHI) that generates novel information about genetic interactions. Guided by strong preliminary data, the proposed research will be guided by two specific aims: 1). Identify and characterize novel targets of TORC1 and TORC2. We will perform CHI using a novel genome-wide approach that incorporates essential and non-essential genes. We will prioritize novel interactions in yeast prioritized by human homologs and unidentified pathways or genes. We will characterize the genes in yeast and human cells 2). Identify novel rapalogs. We will use a computational approach to compare data from CHI with TORC1 to publicly available data and predict potential rapalogs by similarity in genetic interactions, concentrating on human homologs. We will characterize the potential rapalogs in yeast and human cells. The proposed research is innovative because it uses a novel genetic approach in the most tractable model organism and applies it for the first time to TOR biology. The proposed research is significant because it is expected to identify new interactions with TOR and ultimately identify compounds that can be used for medical intervention to modulate TOR activity and impact both healthspan and lifespan. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because there is an urgent need to identify the physiological pathways that interact with TOR and identify new chemical compounds that target the TOR pathway for medical intervention. Thus the research is relevant to the NIH mission and is ultimately expected to positively impact lifespan and healthspan and reduce the burdens of human disabilities.

描述（由申请人提供）：TOR（雷帕霉素的靶标）从酵母到人类在进化上是保守的，并且在控制所有细胞类型的细胞生长方面具有关键作用。我们对与 TOR 相互作用的生理途径以及如何调节这些途径来调节寿命和健康寿命的理解存在根本差距。迫切需要确定描述 TOR 活动的全方位相互作用。长期目标是全面了解 TOR 如何调节细胞生理学。该应用的直接目标是使用系统方法和芽殖酵母酿酒酵母来填补我们对 TOR 活性知识的重要空白。 TOR 复合物的进化保守性与可用于研究芽殖酵母的出色遗传工具相结合，是该应用的核心。中心假设是存在与 TOR 相互作用或受 TOR 调节的生理途径，这些途径尚未被识别，并且从酵母到人类在进化上是保守的。其基本原理是，使用一种新的且未充分利用的遗传方法（称为“复杂单倍体不足”（CHI））将发现新的途径，该方法会生成有关遗传相互作用的新信息。在强有力的初步数据的指导下，拟议的研究将遵循两个具体目标：1）。识别并表征 TORC1 和 TORC2 的新靶点。我们将使用一种新颖的全基因组方法进行 CHI，该方法结合了必需和非必需基因。我们将优先考虑酵母中的新相互作用，优先考虑人类同源物和未识别的途径或基因。我们将表征酵母和人类细胞中的基因 2)。识别新的掠夺者。我们将使用计算方法将 CHI 与 TORC1 的数据与公开数据进行比较，并通过遗传相互作用的相似性预测潜在的 rapalogs，重点关注人类同源物。我们将描述酵母和人类细胞中潜在的rapalogs。拟议的研究具有创新性，因为它在最容易处理的模型生物中使用了一种新颖的遗传方法，并首次将其应用于 TOR 生物学。拟议的研究意义重大，因为它有望确定与 TOR 的新相互作用，并最终确定可用于医疗干预的化合物，以调节 TOR 活性并影响健康寿命和寿命。公共健康相关性：拟议的研究与公共健康相关，因为迫切需要确定与 TOR 相互作用的生理途径，并确定针对 TOR 途径进行医疗干预的新化合物。因此，这项研究与美国国立卫生研究院的使命相关，最终有望对寿命和健康产生积极影响，并减轻人类残疾的负担。