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

基本信息

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
项目类别：
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

项目摘要

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寻找年龄原因的基础上。相关的神经退行性疾病以及针对这些破坏性且很大程度上致命的疾病开发治疗方法该提案的统一主题是关注参与泛素相关质量控制的蛋白质。在神经退行性疾病中，这些途径容易发生相分离和聚集。我们最近在聚谷氨酰胺介导的神经变性和大脑表达的泛素（一类与各种神经退行性疾病有关的蛋白质），我们将应用多标量方法来定义致病机制，强调在寻找新的途径时与泛素依赖性途径的交叉泛素在神经系统中的重要性远远超出了其传统的治疗靶点。确定了泛素-蛋白酶体系统中的降解作用，但更广泛的泛素信号系统是如何的。神经系统疾病造成的损害或响应神经系统疾病而激活代表了当前的重大差距凭借广泛的创新工具/模型和卓越的研究环境，我们。将解决与年龄相关的神经变性广泛相关的基本问题。包括：细胞核中泛素信号改变的影响；泛素改变的贡献；选择性细胞类型和区域脆弱性的稳态以及突变诱导之间的关系；疾病蛋白发生相变的变化、泛素相关途径功能的改变，以及我们通过 R35 获得的发现将有助于定义该复合物。泛素在神经系统疾病中的生物学作用，强调疾病的潜在共同因素发病机制，并确定有希望的治疗靶点，可以推动治疗方法的开发神经退行性疾病。