Alternative Vacuolar Targeting Mechanisms in Yeast

酵母中的替代液泡靶向机制

• 批准号: 8470173
• 负责人: DANIEL J. KLIONSKY
• 金额: $ 63.04万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-06-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8470173
• 关键词: 10 year old; Aging; Autophagocytosis; Autophagosome; Bacterial Infections; Biochemical; Biogenesis; Biology; Cell Death; Cell physiology; Cellular biology; Complex; Cytoplasm; Cytoprotection; Data; Developmental Process; Disease; Drug Targeting; Eating; Elements; Eukaryota; Functional disorder; GLC2 protein; Gastrointestinal Diseases; Generations; Genetic Transcription; Goals; Health; Heart Diseases; Homeostasis; Human; Immunity; Knowledge; Learning; Link; Longevity; Lysosomes; Malignant Neoplasms; Mammals; Membrane; Methods; Microbe; Mitochondria; Mitogen-Activated Protein Kinases; Molecular; Molecular Genetics; Natural Immunity; Nerve Degeneration; Onset of illness; Organelles; Pathway interactions; Phospholipids; Phosphoric Monoester Hydrolases; Phosphotransferases; Physiological Processes; Play; Process; Proteins; Recycling; Regulation; Research; Research Personnel; Role; SNAP receptor; Signal Transduction; Site; Source; Specificity; Symptoms; System; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Translating; Vacuole; Vesicle; Virus Diseases; Yeasts; falls; human disease; innovation; prevent; protein protein interaction; protein transport; research study; response; sensor; trafficking; transcription factor

DESCRIPTION (provided by applicant): Autophagy represents a complex pathway of cellular homeostasis that functions in cytoprotection, but if dysregulated can cause cell death; a complete knowledge of regulation is critical for the potential modulation of this process for therapeutic purposes, and to increase our basic understanding of membrane dynamics and organelle biogenesis. Autophagy occurs in all eukaryotes and the protein components of the autophagic machinery are conserved from yeast to mammals. The hallmark of this process is the formation of double- membrane cytosolic vesicles, autophagosomes that sequester cytoplasmic components. After completion, the autophagosomes fuse with the lysosome/vacuole to release the inner vesicle that is broken down, allowing access to the cargo. Autophagy plays a role in various developmental processes and is associated with a range of pathophysiological conditions. The long-term goal of this proposal is to understand the mechanism and regulation of autophagy and how this translates into autophagosome formation. The molecular field of autophagy is slightly over ten years old, which is startling for a pathway with connections to such a wide range of physiological processes. In a practical sense, this also means there are many questions remaining to be answered. For example, we want to (1) determine how environmental signals are transduced into an autophagic response, defining the kinases, phosphatases and transcription factors that control autophagy; (2) identify the origin of the sequestering vesicle and determine how membrane from a variety of organelles can be commandeered to provide the material needed for autophagosome formation; and (3) understand what regulatory controls determine the switch between specific and non-specific types of autophagy, and the method of achieving cargo specificity. We are using yeast to investigate the molecular mechanism of autophagy; this is the best system for a molecular genetic and biochemical analysis of this complex process. Because of the high degree of conservation, however, the information we learn from yeast will be applicable to higher eukaryotes. At present, over thirty autophagy-related (Atg) proteins have been identified, but their functions and the regulatory processes that control them are largely undefined. The experiments described in this proposal are significant because they will elucidate important links between upstream regulatory components and the machinery that carries out autophagy, providing the next step in a comprehensive analysis that links the signal transduction elements to the functional apparatus, advancing our knowledge of basic cell biology, and identifying targets for ultimate therapeutic intervention. The proposed research is innovative, because it is providing new, and in some cases paradigm-shifting, information about the regulatory and functional components of autophagy.

描述(申请人提供)：自噬是一种复杂的细胞内稳态途径，具有细胞保护功能，但如果失控可能会导致细胞死亡；完整的调控知识对于潜在地调节这一过程以达到治疗目的至关重要，并增加我们对膜动力学和细胞器生物发生的基本理解。自噬存在于所有真核生物中，自噬机制的蛋白质组分从酵母到哺乳动物都是保守的。这一过程的标志是形成双膜胞液小泡，即隔离细胞质成分的自噬小体。完成后，自噬小体与溶酶体/液泡融合，释放被分解的内部小泡，从而进入货物。自噬在不同的发育过程中发挥作用，并与一系列的病理生理条件有关。这项提议的长期目标是了解自噬的机制和调节，以及如何将其转化为自噬形成。自噬的分子场已经有十多年的历史了，对于一个与如此广泛的生理过程有联系的途径来说，这是令人震惊的。在实际意义上，这也意味着还有许多问题有待回答。例如，我们想要(1)确定环境信号如何转化为自噬反应，定义控制自噬的激酶、磷酸酶和转录因子；(2)确定隔离小泡的来源，并确定如何征用各种细胞器的膜来提供自噬形成所需的物质；以及(3)了解哪些调控控制决定了特定类型和非特定类型的自噬之间的切换，以及实现货物特异性的方法。我们正在使用酵母来研究自噬的分子机制；这是对这一复杂过程进行分子遗传和生化分析的最佳系统。然而，由于高度保守，我们从酵母中学到的信息将适用于高等真核生物。目前，已鉴定出30多种自噬相关蛋白，但它们的功能和控制它们的调控过程在很大程度上还不清楚。这项提案中描述的实验具有重要意义，因为它们将阐明上游调节组件与执行自噬的机制之间的重要联系，为将信号转导元件与功能装置联系起来的全面分析提供下一步，促进我们对基础细胞生物学的了解，并确定最终治疗干预的靶点。这项拟议的研究是创新的，因为它提供了关于自噬的调节和功能组成部分的新信息，在某些情况下还改变了范式。