Mechanisms of neurodegenerative diseases: intersections with ubiquitin pathways

神经退行性疾病的机制：与泛素通路的交叉

• 批准号: 10396120
• 负责人: Henry L Paulson
• 金额: $ 108.77万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2029-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10396120
• 关键词: Address; Biological; Brain; Cell Nucleus; Complex; Disease; Elements; Environment; Homeostasis; Impairment; Induced Mutation; Knowledge; Link; Mediating; Modeling; Nerve Degeneration; Nervous system structure; Neurodegenerative Disorders; Pathogenesis; Pathogenicity; Pathway interactions; Phase; Phase Transition; Principal Investigator; Proteins; Quality Control; Research; Role; Signal Transduction; System; Toxic effect; Ubiquitin; age related neurodegeneration; cell type; innovation; multicatalytic endopeptidase complex; nervous system disorder; new therapeutic target; polyglutamine; response; success; therapeutic target; therapy development; tool; ubiquilin

This R35 proposal builds on the principal investigator’s longstanding success seeking the causes of age- related neurodegenerative diseases and developing treatments for these devastating and largely fatal disorders. The proposal’s unifying theme is a focus on proteins that participate in ubiquitin-linked quality control pathways and that are prone, in neurodegenerative diseases, to phase-separate and aggregate. Building on our recent discoveries in polyglutamine-mediated neurodegeneration and brain-expressed ubiquilins (a class of proteins implicated in various neurodegenerative diseases), we will apply multi-scalar approaches to define pathogenic mechanisms, emphasizing intersections with ubiquitin-dependent pathways in the search for novel therapeutic targets. The importance of ubiquitin in the nervous system extends far beyond its classically defined degradative role in the ubiquitin-proteasome system. But how the broader ubiquitin signaling system is impaired by, or activated in response to, diseases of the nervous system represents a significant gap in current knowledge. Leveraging a broad suite of innovative tools/models and an exceptional research environment, we will address fundamental issues of broad relevance to age-related neurodegeneration. These topical issues include: the impact of altered ubiquitin signaling in the nucleus; the contribution of altered ubiquitin homeostasis to selective cell type and regional vulnerability; and the relationship between mutation-induced changes in phase transitions undertaken by disease proteins, altered function in ubiquitin-linked pathways, and toxicity in the nervous system. The discoveries we make through the R35 will help define the complex biological roles of ubiquitin in diseases of the nervous system, highlight potential shared elements of disease pathogenesis, and identify promising therapeutic targets that could drive the development of treatments for neurodegenerative disorders.

这项R35提案建立在首席研究员长期成功地寻找年龄原因的基础上