Nuclear and Glial Dysfunction in Neurodegeneration

神经退行性变中的核和神经胶质功能障碍

• 批准号: 10664230
• 负责人: Jeffrey D Rothstein
• 金额: $ 122.81万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-16 至 2031-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10664230
• 关键词: ALS patients; Aging; Astrocytes; Biological Models; Biology; C9ALS; C9ORF72; Cell Line; Cellular biology; Data; Defect; Degenerative Disorder; Dementia; Dendrites; Development; Disease; Disease Marker; Drosophila genus; Educational process of instructing; Elements; Functional disorder; Future; Health; Human; Huntington Disease; Induced pluripotent stem cell derived neurons; Injury; Learning; Link; Location; Modeling; Motor Neurons; Mutation; Nerve Degeneration; Nervous System Trauma; Neurodegenerative Disorders; Neuroglia; Neurons; Nuclear; Nuclear Pore; Nuclear Pore Complex; Pathogenicity; Pathology; Pathway interactions; Patients; Process; Property; Proteins; Rodent; Subgroup; Synapses; System; Therapeutic; Validation; Vertebral column; brain tissue; candidate identification; cell type; drug action; drug discovery; fly; frontotemporal lobar dementia amyotrophic lateral sclerosis; human disease; in vivo; induced pluripotent stem cell; insight; loss of function; molecular subtypes; mouse model; mutant; novel therapeutics; nucleocytoplasmic transport; protein TDP-43; repaired; sporadic amyotrophic lateral sclerosis; therapeutic candidate; tool

Abstract In the last 5–10-years new model systems, to study ALS, FTD and other dementias, based on patient derived induced pluripotent cell lines have provide great insight into highly relevant disease-causing pathways as well as fundamental neuronal and glial cell biology. New studies using these, and other model systems suggest the nuclear transport is the fundamental injury linked to both familial sporadic ALS and FTD. Emerging studies now implicate nuclear transport and the nuclear pore complex in multiple different neurodegenerative diseases including ALS, FTD, Huntington’s disease and even aging. These studies are beginning to identify candidate therapies for sporadic forms of the disease. The nuclear pore complex is diverse, and mutations of its constituent proteins can lead to a wide range of different degenerative diseases. Thus, studies of the CNS nuclear pore and nucleocytoplasmic transport have pathogenic implications that are wide ranging. This proposal will comprehensively investigate the biology of CNS nuclear pores and nuclear transport- the fundamental properties in different neuronal and glia, mechanisms by which the nuclear pore is disrupted, include possibly disease initiating biology involving the ESCT3/CHMP7 pathways, how the nuclear pore complex is disrupted in sporadic and familial forms of the diseases utilizing several complementary models including C9-ALS fly and mouse models and iPS neurons and brain tissue from sporadic and C9orf72 mutant ALS/FTD patients. We will also investigate whether modulation of nucleocytoplasmic transport and /or repair of the nuclear pore complex may be a therapeutic strategy for ALS/FTD. Our emerging data teach that there are multiple candidate therapeutic opportunities for this pathway and neurodegeneration. As we have now learned that defect on the nuclear pore complex are upstream of the disruption of TDP43 nuclear location and loss of function, this pathway may have relevance to not only ALS and FTD – but other neurological injuries involving TDP43 misregulation. Finally, studies over the last decade have revealed that neurodegenerative diseases are not simply a disorder of neurons, but that glial cells also contribute to pathophysiology. Many studies have implicated aberrant astroglial function in ALS and neurodegeneration. Regional alterations of astroglia have long been known—but how this occurs and whether astroglia exist as functional/molecular subtypes has been unclear. New studies from our group and others now suggests real subtypes of astroglia exist, may have specific functions n modulating cortical dendritic and synaptic biology and may be selectively altered in ALS. The biology of these newly identified subgroups will be explored in this proposal and how they alter spines/dendrites, neuronal elements known to be dramatically altered in neurodegeneration.

抽象的 在过去 5-10 年的新模型系统中，基于患者衍生的数据来研究 ALS、FTD 和其他痴呆症 诱导多能细胞系也为高度相关的致病途径提供了深入的见解 使用这些和其他模型系统的新研究表明，作为基础神经和神经胶质细胞生物学。 核转运是与家族性散发性 ALS 和新兴 FTD 相关的根本损伤。 现在的研究表明多种不同神经退行性疾病中的核运输和核孔复合体 这些研究已开始确定 ALS、FTD、亨廷顿氏舞蹈病甚至衰老等疾病。 散发性疾病的候选疗法核孔复合体是多种多样的，并且突变。 其组成蛋白可导致多种不同的退行性疾病，因此，对中枢神经系统的研究。 核孔和核质运输具有广泛的致病影响。 该提案将全面研究中枢神经系统核孔和核运输的生物学—— 不同神经和神经胶质细胞的基本特性，核孔被破坏的机制， 包括可能涉及 ESCT3/CHMP7 途径的疾病起始生物学、核孔如何 利用几种互补模型破坏散发性和家族性疾病的复合体 包括来自散发性和 C9orf72 突变体的 C9-ALS 果蝇和小鼠模型以及 iPS 神经元和脑组织 我们还将研究核细胞质运输和/或修复的调节。 我们的新数据表明，核孔复合物的研究可能是 ALS/FTD 的一种治疗策略。 正如我们现在所拥有的，该途径和神经退行性疾病有多种候选治疗机会。 了解到核孔复合体上的缺陷是 TDP43 核位置破坏的上游，并且 功能丧失，该通路可能不仅与 ALS 和 FTD 有关，还与其他神经系统疾病有关 最后，过去十年的研究表明，神经退行性疾病会导致 TDP43 失调。 疾病不仅仅是神经元的疾病，神经胶质细胞也有助于许多病理生理学。 研究表明星形胶质细胞功能异常与 ALS 和神经退行性变有关。 星形胶质细胞早已为人所知，但它是如何发生的以及星形胶质细胞是否作为功能/分子存在 我们小组和其他人的新研究现在表明了星形胶质细胞的真正亚型。 存在，可能具有调节皮质树突和突触生物学的特定功能，并且可以选择性地 本提案将探讨这些新发现的亚群的生物学变化以及它们如何改变。 改变棘/树突，这些神经元在神经退行性疾病中起着显着的作用。