The mechanism and regulation of autophagy

自噬的机制和调控

• 批准号: 10408006
• 负责人: DANIEL J. KLIONSKY
• 金额: $ 76.58万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10408006
• 关键词: Affect; Autophagocytosis; Autophagosome; Bacterial Infections; Biochemical; Biogenesis; Cell Death; Cellular biology; Complex; Cytoprotection; Developmental Process; Diabetes Mellitus; Disease; Elements; Eukaryota; Fetal Development; Functional disorder; Gastrointestinal Diseases; Goals; Heart Diseases; Homeostasis; Human; Knowledge; Learning; Link; Lysosomes; Malignant Neoplasms; Mammals; Membrane; Molecular; Molecular Genetics; Mutation; Natural Immunity; Nerve Degeneration; Onset of illness; Organelles; Pathway interactions; Physiological Processes; Play; Process; Proteins; Regulation; Research; Role; Signal Transduction; Structure; Symptoms; System; Therapeutic; Therapeutic Intervention; Time; Tissues; Vacuole; Vesicle; Virus Diseases; Yeasts; experimental study; human disease; innovation; prevent

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 contain cytoplasmic components sequestered by the phagophore, a unique transient compartment. 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 goals of this proposal are to understand the mechanism of action of the autophagy- related proteins, how the process is regulated, and why specific mutations result in human disease. In the last 20 years, we have learned much about the molecular aspects of autophagy—42 autophagy- related (Atg) proteins have been identified, but we only have a cursory knowledge of their function. In addition, autophagic dysfunction is associated with numerous diseases in humans, including cancer, heart disease and neurodegeneration. Although autophagy is primarily cytoprotective, excessive autophagy is detrimental. Thus, we need a full understanding of the regulatory network in order to apply therapeutic interventions aimed at treating disease through autophagy modulation. In the next five years, we want to (1) understand the structure and function of the Atg proteins; (2) define the regulatory controls that allow autophagy induction, determine the switch between specific and non-specific types of autophagy, and maintain autophagy at appropriate levels; and (3) decipher the relationship between mutations affecting autophagy and diseases, with an ultimate goal of facilitating treatment. 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 more complex eukaryotes. 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.

自噬是一种复杂的细胞内稳态途径，具有细胞保护作用，但如果 失调可导致细胞死亡;完整的调控知识对于潜在的调节至关重要。 这一过程的治疗目的，并增加我们对膜动力学的基本理解， 细胞器生物发生自噬发生在所有的真核生物中，自噬的蛋白质成分 从酵母到哺乳动物，机器都是保守的。这一过程的标志是形成双- 膜胞质小泡，自噬体，含有细胞质成分， 噬菌体，一个独特的短暂的隔间。完成后，自噬体与 在一些实施方案中，细胞可以通过溶酶体/空泡释放被分解的内囊泡，从而允许接近货物。自噬 在各种发育过程中发挥作用，并与一系列病理生理学 条件这项提案的长期目标是了解自噬的作用机制- 相关的蛋白质，该过程是如何调节的，以及为什么特定的突变会导致人类疾病。 在过去的20年里，我们已经了解了很多关于自噬的分子方面-42自噬- 已经鉴定出了与此相关的（Atg）蛋白，但我们对其功能只有粗略的了解。此外，本发明还提供了一种方法， 自噬功能障碍与人类的许多疾病有关，包括癌症、心脏病和 神经变性虽然自噬主要是细胞保护性的，但过度的自噬是有害的。因此，在本发明中， 我们需要充分了解调节网络，以便应用治疗干预措施， 通过自噬调节治疗疾病。在接下来的五年里，我们希望（1）了解结构 和功能的Atg蛋白;（2）定义的调控，允许自噬诱导，确定 特异性和非特异性自噬类型之间的转换，并维持自噬在适当的 水平;（3）破译影响自噬的突变与疾病之间的关系， 最终目的是促进治疗。我们正在利用酵母研究 自噬;这是对这一复杂过程进行分子遗传学和生物化学分析的最佳系统。 然而，由于高度的保守性，我们从酵母中学到的信息将是适用的 到更复杂的真核生物。 本提案中描述的实验意义重大，因为它们将阐明重要的联系 上游调控元件和进行自噬的机器之间的联系，提供了下一个 在将信号转导元件与功能装置联系起来的综合分析中的步骤， 推进我们对基本细胞生物学的了解，并确定最终治疗干预的目标。 拟议的研究是创新的，因为它提供了新的，在某些情况下，范式转移， 关于自噬的调节和功能成分的信息。