Novel molecular targets within the TOR pathway

描述(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，在所有类型的细胞中都具有控制细胞生长的关键作用。我们对与TOR相互作用的生理途径以及调节这些途径如何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活动的全部相互作用范围。长期目标是对TOR如何调节细胞生理学有一个完整的了解。这项应用的直接目标是使用系统方法和萌芽酵母酿酒酵母来填补我们对TOR活性知识的重要空白。TOR复合体的进化保守，加上可用于研究发芽酵母的杰出遗传工具，是这一应用的核心。中心假设I认为，存在与TOR相互作用或受TOR调控的生理途径，这些途径尚未确定，并将从酵母到人类在进化上保守。其基本原理是，将使用一种新的、未得到充分利用的遗传方法来发现新的途径，该方法称为“复杂单倍体不足”(CHI)，它产生关于遗传相互作用的新信息。在强大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TORC1和TORC2的新靶点。我们将使用一种新的全基因组方法来执行CHI，该方法结合了必需和非必需基因。我们将根据人类同源物和未知的途径或基因优先考虑酵母中的新相互作用。我们将对酵母和人类细胞中的基因进行表征。辨别新奇的拉帕罗格。我们将使用计算方法将CHI和TORC1的数据与公开可用的数据进行比较，并根据遗传相互作用中的相似性预测潜在的Rapalog，重点是人类同源基因。我们将描述酵母和人类细胞中潜在的拉帕罗格。这项拟议的研究具有创新性，因为它在最易驯化的模式生物体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的化合物，以调节TOR活动并影响健康和寿命。 公共卫生相关性：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途径的新化合物进行医疗干预。因此，这项研究与美国国立卫生研究院的任务相关，最终有望对寿命和健康水平产生积极影响，并减轻人类残疾的负担。

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.