Ataxin-2 complex proteins in neurodegeneration.

神经变性中的 Ataxin-2 复合蛋白。

基本信息

批准号：
10612474
负责人：
Stefan M. PULST
金额：
$ 93.03万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-01 至 2030-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10612474
关键词：
Address Adult Affect Animal Model Animals Apoptotic Ataxia Autophagocytosis Award Behavioral Cells Cerebellar degeneration Cessation of life Chemicals Complex Cytoplasm Deterioration Dimensions Disease Environment Foundations Funding Gene Targeting Genes Grant Heat shock proteins Human In Vitro Inherited Laboratories Mediating Modeling Morphology Motor Neuron Disease Motor Neurons Nerve Degeneration Neurodegenerative Disorders Neurons Nutrient Pathogenicity Phase Physiological Principal Investigator Proteins Proteomics Purkinje Cells RNA Transport RNA metabolism RNA-Binding Proteins Regulation Reproducibility Research Resource Sharing Role SCA2 protein Scientist Signal Transduction Small RNA Spinal Spinocerebellar Ataxias Stress Techniques Time Translations Vertebral column diversity and inclusion dosage experimental study genome-wide human model in vivo innovation insight muscle strength mutant neuron loss novel polyglutamine protein complex protein function response small molecule success therapeutic target tool transcriptomics

项目摘要

Project Summary/Abstract This R35 proposal builds on experiments supported by a Javits R37 and a U01 CREATE Bio award and the longstanding success of the principal investigator’s group leading from mechanistic discoveries in spinocerebellar ataxias and translation to novel treatments, one of which is now in a phase 1 human trial (BIIB105). The proposal’s unifying theme is a focus on RNA-binding proteins (RBPs) in the ATXN2-complex of proteins that direct several aspects of RNA metabolism and that are prone to phase-separation and aggregation. Building on our recent discoveries in polyglutamine-mediated neurodegeneration and neuronal staufen-1 (STAU1) overabundance, we will apply multi-dimensional approaches to define novel pathogenic mechanisms in their intersections with autophagy, the unfolded protein response (UPR), and with RNA metabolism and transport. We postulate that these responses, while compensatory in the short term, become maladaptive with sustained stress and that an RBP network response leads to progressive deterioration of autophagic flux and amplification of apoptotic signaling. We have established a broad suite of innovative tools and unique models in an exceptional research environment with established local and national collaborators with whom we have shared resources over many years. Our approach has been to characterize cerebellar degeneration at multiple time points using genome-wide transcriptomic, proteomic, morphologic, physiologic and behavioral techniques. These foundations will allow us to rapidly progress from cellular to animal models modifying dosage of specific genes in vitro and in vivo. We will now extend this approach from Purkinje cells to spinal motor neurons enabling us to address fundamental issues of broad relevance to inherited and sporadic neurodegenerative diseases. These topical issues include: the role of cytoplasmic RBPs, especially ATXN2 and STAU1, in response to nutrient, chemical and mutant protein stress; their regulation and interplay with each other, and key proteins determining autophagic flux and the UPR; their overall effect on neuronal death; and finally, their promise as therapeutic targets using small molecules and RNA-directed therapies. R35 funding will allow us to identify novel functions of proteins in the ATXN2-complex in neurodegeneration and define shared features across different neurodegenerative diseases with particular relevance not only to inherited, but also to sporadic forms of ataxia and motor neuron disease. The broad scope of our proposed studies will enable participation of scientists with diverse backgrounds in a laboratory and departmental culture of inclusivity and diversity. With our established commitment to reproducibility of animal models and gene targeting approaches, the novel mechanistic insights hold promise for translation into developing novel treatments for neurodegenerative disorders.

项目概要/摘要该 R35 提案建立在 Javits R37 和 U01 CREATE Bio 奖以及首席研究员团队在机械发现方面取得了长期成功脊髓小脑性共济失调和新疗法的转化，其中一种疗法目前正在进行第一阶段人体试验 (BIIB105) 该提案的统一主题是 ATXN2 复合物中的 RNA 结合蛋白 (RBP)。指导 RNA 代谢多个方面且易于发生相分离的蛋白质基于我们最近在聚谷氨酰胺介导的神经变性和神经元方面的发现。 staufen-1 (STAU1) 过多，我们将应用多维方法来定义新的致病菌与自噬、未折叠蛋白反应 (UPR) 和 RNA 交叉的机制我们假设这些反应虽然在短期内是补偿性的，但会变成。持续压力的适应不良以及 RBP 网络反应导致逐渐恶化我们已经建立了一套广泛的创新工具。与当地和国家合作者在特殊的研究环境中建立独特的模型我们多年来与他们共享资源，我们的方法是描述小脑的特征。使用全基因组转录组、蛋白质组、形态学、生理学在多个时间点进行变性这些基础将使我们能够快速从细胞模型发展到动物模型。我们现在将这种方法从浦肯野细胞扩展到体内和体外修改特定基因的剂量。脊髓运动神经元使我们能够解决与遗传性和散发性广泛相关的基本问题这些热门问题包括：细胞质 RBP，尤其是 ATXN2 的作用。 STAU1，响应营养、化学和突变蛋白胁迫，它们的调节和相互作用；相互之间，以及决定自噬通量和 UPR 对神经元死亡的总体影响的关键蛋白质；最后，他们承诺使用小分子和 RNA 导向疗法 R35 作为治疗靶点。资金将使我们能够确定 ATXN2 复合物中蛋白质在神经退行性变和定义不同神经退行性疾病的共同特征，不仅与特定相关遗传性的，也涉及散发性的共济失调和运动神经元疾病。我们提出的范围广泛。研究将使具有不同背景的科学家参与实验室和部门文化我们对动物模型和基因的可重复性的既定承诺。针对方法，新颖的机制见解有望转化为开发新颖的方法神经退行性疾病的治疗。