SNARE-mediated membrane fusion involved in autophagosome biogenesis

SNARE 介导的膜融合参与自噬体生物发生

• 批准号: 10006587
• 负责人: Jiajie Diao
• 金额: $ 36.6万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10006587
• 关键词: Autophagocytosis; Autophagosome; Biogenesis; Development; Diabetes Mellitus; Disease; Functional disorder; Future; Human; Investigation; Longevity; Malignant Neoplasms; Mediating; Membrane Fusion; Membrane Fusion Activity; Modification; Molecular; Morphology; Neurodegenerative Disorders; Nuclear Receptors; Pathway interactions; Process; Proteins; Quality Control; Role; SNAP receptor; Stress; Therapeutic; base; drug development; human disease; novel therapeutic intervention; receptor binding; reconstitution; response; wasting

PROJECT SUMMARY Autophagy is a crucial catabolic pathway by which cellular waste is recycled. Autophagic dysfunction has been implicated in cellular quality control, responses to stress, development, lifespan, and a range of infectious and other diseases in humans, including cancer, neurodegenerative diseases, and diabetes. Membrane fusion is a critical process involved in autophagosome biogenesis. The exact molecular mechanism of autophagic membrane fusion remains far from clear and thus a major topic of investigation. Since membrane fusion activity could act as a switch to spatially and temporally regulate the autophagic flux in human diseases due to its dysregulation, dissecting the fusion machinery is essential to understanding the exact roles of autophagy in specific disease contexts. Therefore, studying the regulatory mechanism of membrane fusion will provide the opportunity to develop new therapeutic strategies in order to control activity of autophagy. Based on our preliminary findings, we hypothesize that the morphology and modification status of autophagic SNAREs are important for mediating membrane fusion involved in autophagosome biogenesis, while this process is regulated by accessory proteins including nuclear receptor binding factor 2 and Atg9. Further systematical studies on the role of SNARE-mediated membrane fusion in autophagosome maturation and initiation are critical to elucidate detailed molecular mechanisms, which could offer therapeutic advances. Moreover, an attempt to find new fusogens and reconstitute the early autophagosome biogenesis is an important expansion, which is also essential for future drug development.

项目摘要 自噬是细胞废物回收的重要分解代谢途径。自噬功能障碍 与细胞质量控制、对压力的反应、发育、寿命和一系列的 人类的传染病和其他疾病，包括癌症、神经退行性疾病和糖尿病。 膜融合是自噬体生物发生的关键过程。的确切分子 自噬膜融合的机制仍远不清楚，因此是一个主要的研究课题。 由于膜融合活性可以作为一个开关，在空间和时间上调节自噬通量 在人类疾病中，由于其失调，解剖融合机制对于理解 自噬在特定疾病中的确切作用。因此，研究其调控机制， 膜融合将为开发新的治疗策略提供机会， 自噬活性。根据我们的初步发现，我们假设，形态和 自噬SNARE的修饰状态对于介导参与的膜融合是重要的， 自噬体的生物合成，而这一过程是由辅助蛋白，包括核 受体结合因子2和Atg 9。对SNARE介导的膜的作用的进一步系统研究 自噬体成熟和起始中的融合对于阐明详细的分子机制至关重要， 可以提供治疗进展。此外，寻找新的融合子和重组 早期自噬体的生物合成是一个重要的扩展，这也是未来药物治疗的必要条件。 发展