Novel molecular targets within the TOR pathway

描述（由申请人提供）：TOR（雷帕霉素靶标）在从酵母到人类的进化中是保守的，在所有细胞类型中控制细胞生长具有关键作用。我们对与TOR相互作用的生理通路以及调节这些通路如何调节寿命和健康的理解存在根本性的差距。迫切需要确定描述职权范围活动的各种相互作用。长期目标是全面了解TOR如何调节细胞生理学。本申请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活性的认识中的重要空白。TOR复合物的进化保守性加上可用于研究芽殖酵母的杰出遗传工具是该应用的核心。中心假设是存在与TOR相互作用或受TOR调节的生理途径，这些生理途径是未鉴定的，并且从酵母到人类在进化上是保守的。其基本原理是，新的途径将被发现使用一种新的和未充分利用的遗传方法称为“复杂的单倍不足”（CHI），产生新的信息遗传相互作用。在强有力的初步数据的指导下，拟议的研究将以两个具体目标为指导：1）。识别和表征TORC 1和TORC 2的新靶点。我们将使用一种新的全基因组方法进行CHI，该方法将必需基因和非必需基因结合起来。我们将优先考虑新的相互作用在酵母优先由人类同源物和不明途径或基因。我们将描述酵母和人类细胞中的基因2）。鉴定新型雷帕霉素类似物。我们将使用计算方法比较CHI与TORC 1的数据与公开可用的数据，并通过遗传相互作用的相似性预测潜在的rapalogs，集中在人类同源物上。我们将在酵母和人类细胞中表征潜在的雷帕霉素类似物。这项研究具有创新性，因为它在最易处理的模式生物中使用了一种新的遗传方法，并首次将其应用于TOR生物学。这项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以调节TOR活性并影响健康寿命和寿命的化合物。

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.