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

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

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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.

项目摘要/摘要该R35提案建立在Javits R37和U01创建Bio Award的实验基础上主要研究者小组的长期成功，从机械发现中引起脊椎动物的共济失调和转化为新疗法，其中之一是在1阶段的人类试验中（BIIB105）。该提案的统一主题是关注ATXN2复合物中的RNA结合蛋白（RBP）指导RNA代谢的多个方面的蛋白质，容易出现相分开和聚合。建立在我们最近在多谷氨酸介导的神经变性和神经元中发现的基础 Staufen-1（stau1）过度，我们将采用多维方法来定义新的致病性与自噬，展开的蛋白质反应（UPR）和RNA相交的机制代谢和运输。我们假设这些回应在短期内进行补偿，但适应不良的持续压力，RBP网络响应导致了渐进的亲戚自噬通量和凋亡信号的扩增。我们已经建立了一系列创新工具以及与既定的本地和国家合作者的杰出研究环境中的独特模型多年来，我们与我们共享资源。我们的方法是描述小脑使用全基因组转录组，蛋白质组学，形态学，生理学的多个时间点变性和行为技术。这些基础将使我们能够从细胞到动物模型迅速发展在体外和体内修饰特定基因的剂量。现在，我们将将这种方法从Purkinje单元扩展到脊柱运动神经元使我们能够解决与继承和弹性的广泛相关性的基本问题神经退行性疾病。这些局部问题包括：细胞质RBP的作用，尤其是ATXN2 和stau1，响应营养，化学和突变蛋白胁迫；他们与彼此，以及确定自噬通量和UPR的关键蛋白质；它们对神经元死亡的总体影响；最后，使用小分子和RNA指导的疗法作为治疗靶标的承诺。 R35 资金将使我们能够在ATXN2复合物中确定蛋白质的新功能在不同的神经退行性疾病中定义的共享特征，不仅与继承，但也属于零星的共济失调和运动神经元疾病。我们提议的广泛范围研究将使具有潜水员背景的科学家参与实验室和部门文化包容性和多样性。我们对动物模型和基因可重复性的既定承诺靶向方法，新颖的机械见解有望转化为发展新颖神经退行性疾病的治疗方法。