MOLECULAR MECHANISM OF MAMMALIAN AUTOPHAGY

哺乳动物自噬的分子机制

• 批准号: 8168254
• 负责人: Qingjun Wang
• 金额: $ 34.91万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8168254
• 关键词: Aging; Animals; Autophagocytosis; Biochemical; Biological; Biological Markers; Cells; Computer Retrieval of Information on Scientific Projects Database; Data; Development; Diagnostic; Funding; Genetic; Goals; Grant; Human; Infection; Institution; Life; Liver diseases; Malignant Neoplasms; Mammals; Mediating; Molecular; Mus; Myopathy; Nerve Degeneration; Organelles; Pathology; Pathway interactions; Patients; Physiology; Play; Preventive; Proteins; Proteomics; Recycling; Regulation; Reporting; Research; Research Personnel; Resources; Role; Source; Therapeutic Intervention; Tumor Suppression; United States National Institutes of Health; Work; human disease; insight; novel; protein protein interaction; therapeutic target

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. As a ubiquitous lysosomal pathway essential for degrading and recycling proteins and organelles, autophagy has been implicated in a broad spectrum of human disease including cancer, infection, liver disease, myopathy and neurodegeneration. However, the molecular machinery comprising the mammalian autophagy pathway and the molecular mechanism of how this machinery functions are largely unknown. Our long-term goal is to understand the molecular mechanism of the mammalian autophagy pathway and its relevance to human disease, for discovering much needed early diagnostic biomarkers and therapeutic targets. To achieve this goal, our overall objective is to first identify novel protein-protein interactions in the mammalian autophagy pathway and subsequently to determine the functions of these novel interactors. Beclin 1, the first reported mammalian autophagy protein, plays an important positive role in autophagy regulation and has been implicated in a variety of human physiology and pathology, including tumor suppression, neurodegeneration, development and aging. Therefore, for this study, we will investigate Beclin 1-mediated autophagy regulation so as to begin deciphering the molecular mechanism of mammalian autophagy. Guided by strong preliminary data, three specific aims will be pursued using a combination of a novel integrated mouse genetic-proteomic approach as well as biochemical and cell biological studies. In Aim 1, we will establish the framework of a context-dependent mammalian autophagy interactome through identifying Beclin 1-interacting proteins from living animals; in Aim 2, we will elucidate the molecular details of autophagy regulation by two novel Beclin 1-interacting proteins, Atg14L and Rubicon; and in Aim 3, we will explore the molecular details of autophagy regulation by a third novel Beclin 1-interactor and its cancer relevance. By establishing the framework of the mammalian autophagy interactome and unraveling the molecular details of autophagy regulation by Beclin 1 and its interacting proteins, this proposed work will not only provide insight into the role of autophagy in mammals but also generate novel potential targets for preventive and therapeutic interventions that may ultimately aid patients suffering from autophagy-related human disease.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 作为一种普遍存在的溶酶体途径，对于降解和回收蛋白质和细胞器至关重要，自噬与多种人类疾病有关，包括癌症、感染、肝病、肌病和神经变性。然而，组成哺乳动物自噬途径的分子机制以及该机制如何发挥作用的分子机制在很大程度上尚不清楚。我们的长期目标是了解哺乳动物自噬途径的分子机制及其与人类疾病的相关性，以发现急需的早期诊断生物标志物和治疗靶点。为了实现这一目标，我们的总体目标是首先确定哺乳动物自噬途径中新的蛋白质-蛋白质相互作用，然后确定这些新相互作用子的功能。 Beclin 1是第一个报道的哺乳动物自噬蛋白，在自噬调节中发挥着重要的积极作用，并与多种人类生理和病理有关，包括肿瘤抑制、神经退行性变、发育和衰老。因此，在本研究中，我们将研究Beclin 1介导的自噬调控，以破译哺乳动物自噬的分子机制。在强有力的初步数据的指导下，将结合新型小鼠遗传蛋白质组学方法以及生化和细胞生物学研究来实现三个具体目标。在目标 1 中，我们将通过鉴定来自活体动物的 Beclin 1 相互作用蛋白，建立背景依赖性哺乳动物自噬相互作用组的框架；在目标 2 中，我们将阐明两种新型 Beclin 1 相互作用蛋白 Atg14L 和 Rubicon 调节自噬的分子细节；在目标 3 中，我们将探索第三种新型 Beclin 1 相互作用物调节自噬的分子细节及其与癌症的相关性。通过建立哺乳动物自噬相互作用组的框架并揭示 Beclin 1 及其相互作用蛋白调节自噬的分子细节，这项工作不仅将深入了解自噬在哺乳动物中的作用，而且还将产生新的潜在预防和治疗靶点干预措施最终可能会帮助患有自噬相关人类疾病的患者。