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:10450573
- 负责人:
- 金额:$ 93.03万
- 依托单位:
- 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:
- 关键词:AddressAdultAffectAnimal ModelAnimalsApoptoticAtaxiaAutophagocytosisAwardBehavioralCellsCerebellar degenerationCessation of lifeChemicalsComplexDeteriorationDiseaseEnvironmentFoundationsFundingGene TargetingGenesGrantHeat shock proteinsHumanIn VitroInheritedLaboratoriesMediatingModelingMorphologyMotor Neuron DiseaseMotor NeuronsNerve DegenerationNeurodegenerative DisordersNeuronsNutrientPathogenicityPhasePhysiologicalPrincipal InvestigatorProteinsProteomicsPurkinje CellsRNA TransportRNA metabolismRNA-Binding ProteinsRegulationReproducibilityResearchResource SharingRoleSCA2 proteinScientistSignal TransductionSmall RNASpinalSpinocerebellar AtaxiasStressTechniquesTimeTranslationsdiversity and inclusiondosageexperimental studygenome-widehuman modelin vivoinnovationinsightmuscle strengthmutantneuron lossnovelpolyglutamineprotein complexprotein functionresponsesmall moleculesuccesstherapeutic targettooltranscriptomics
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.
项目总结/摘要
该R35提案建立在Javits R37和U 01 CREATE Bio奖支持的实验基础上,
长期以来,主要研究人员的小组从机械发现中取得了成功,
脊髓小脑共济失调和翻译到新的治疗方法,其中一个现在是在第一阶段的人体试验
(BIIB105)。该提案的统一主题是关注ATXN 2复合物中的RNA结合蛋白(RBP),
指导RNA代谢的几个方面并且易于相分离的蛋白质,
聚合来基于我们最近在聚谷氨酰胺介导的神经变性和神经元变性方面的发现,
staufen-1(STAU 1)过量,我们将应用多维度的方法来定义新的致病性
与自噬、未折叠蛋白反应(UPR)和RNA相互作用的机制
代谢和运输。我们假设这些反应虽然在短期内是补偿性的,
适应不良与持续的压力和RBP网络的反应导致进行性恶化,
自噬通量和细胞凋亡信号的放大。我们已经建立了一套广泛的创新工具
和独特的模型在一个特殊的研究环境与建立当地和国家的合作者
多年来我们一直与他们共享资源。我们的方法是描述小脑
使用全基因组转录组学、蛋白质组学、形态学、生理学和生物学方法,
和行为技术。这些基础将使我们能够从细胞模型快速发展到动物模型
在体外和体内改变特定基因的剂量。我们现在将这种方法从浦肯野细胞扩展到
脊髓运动神经元使我们能够解决与遗传性和散发性疾病广泛相关的基本问题,
神经退行性疾病这些热点问题包括:细胞质RBP的作用,特别是ATXN 2
和STAU 1,响应营养,化学和突变蛋白质胁迫;它们的调节和相互作用,
相互作用,以及决定自噬通量和UPR的关键蛋白质;它们对神经元死亡的总体影响;
最后,它们有望成为小分子和RNA导向疗法的治疗靶点。R35
资金将使我们能够确定ATXN 2复合物中蛋白质在神经变性中的新功能,
定义不同神经退行性疾病的共同特征,不仅与
运动神经元疾病是一种遗传性疾病,但也与散发性共济失调和运动神经元疾病有关。我们建议的广泛范围
研究将使具有不同背景的科学家能够参与实验室和部门文化
包容性和多样性。凭借我们对动物模型和基因的可重复性的既定承诺,
针对性的方法,新的机械见解有希望翻译成开发新的
神经退行性疾病的治疗。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Stefan M. PULST其他文献
Stefan M. PULST的其他文献
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{{ truncateString('Stefan M. PULST', 18)}}的其他基金
Targeting STAU1 for TDP-43 proteinopathies
靶向 STAU1 治疗 TDP-43 蛋白病
- 批准号:
10512615 - 财政年份:2022
- 资助金额:
$ 93.03万 - 项目类别:
Ataxin-2 complex proteins in neurodegeneration.
神经变性中的 Ataxin-2 复合蛋白。
- 批准号:
10612474 - 财政年份:2022
- 资助金额:
$ 93.03万 - 项目类别:
Antisense Oligonucleotides for treating Spinocerebellar Ataxia Type 2
用于治疗 2 型脊髓小脑共济失调的反义寡核苷酸
- 批准号:
9912849 - 财政年份:2018
- 资助金额:
$ 93.03万 - 项目类别:
Characterization of ATXN2 as a target for ALS in SCA2 motor neurons
ATXN2 作为 SCA2 运动神经元 ALS 靶标的表征
- 批准号:
9601486 - 财政年份:2018
- 资助金额:
$ 93.03万 - 项目类别:
Comp B-Western Intermountain Regional NMD STARnet
比较 B-西部山间区域 NMD STARnet
- 批准号:
8915498 - 财政年份:2014
- 资助金额:
$ 93.03万 - 项目类别:
Comp B-Western Intermountain Regional NMD STARnet
比较 B-西部山间区域 NMD STARnet
- 批准号:
8821956 - 财政年份:2014
- 资助金额:
$ 93.03万 - 项目类别:
Identification of mutation causing Purkinje cell degeneration in the shaker rat
引起摇床大鼠浦肯野细胞变性的突变的鉴定
- 批准号:
8512375 - 财政年份:2013
- 资助金额:
$ 93.03万 - 项目类别:
Antisense oligonucleotides for the treatment of spinocerebellar ataxia type 2
用于治疗 2 型脊髓小脑共济失调的反义寡核苷酸
- 批准号:
8683274 - 财政年份:2013
- 资助金额:
$ 93.03万 - 项目类别:
Antisense oligonucleotides for the treatment of spinocerebellar ataxia type 2
用于治疗 2 型脊髓小脑共济失调的反义寡核苷酸
- 批准号:
8584105 - 财政年份:2013
- 资助金额:
$ 93.03万 - 项目类别:
Drug Discovery for Spinocerebellar Ataxia Type 2 (SCA2)
治疗 2 型脊髓小脑共济失调 (SCA2) 的药物发现
- 批准号:
8047349 - 财政年份:2010
- 资助金额:
$ 93.03万 - 项目类别:
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