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，根据患者得出 诱导的多能细胞系也为高度相关的致病途径提供了深入的了解 作为基本神经元和神经胶质细胞生物学。使用这些的新研究以及其他模型系统建议 核运输是与家庭零星ALS和FTD有关的根本伤害。新兴 现在的研究暗示了多种不同神经退行性的核转运和核孔复合物 包括ALS，FTD，亨廷顿氏病甚至衰老在内的疾病。这些研究开始识别 疾病零星形式的候选疗法。核孔复合物是潜水员， 它的成分蛋白会导致广泛的不同退化性疾病。那是CNS的研究 核孔，核孔和核巨质转运具有广泛范围的致病意义。这 提案将全面研究中枢神经系统核孔和核运输的生物学 - 不同神经元和神经胶质的基本特性，核孔被破坏的机制， 包括可能的疾病启动涉及ESCT3/CHMP7途径的生物学，核孔如何 复杂的疾病的零星和家庭形式破坏了使用几种完整模型 包括偶发和C9ORF72突变体的C9-ALS蝇和小鼠模型以及IPS神经元以及脑组织 ALS/FTD患者。我们还将调查核细胞质运输和 /或修复的调节 核孔复合物的可能是ALS/FTD的治疗策略。我们的新兴数据教学 是该途径和神经变性的多种候选治疗机会。就像我们现在有 得知核孔复合物的缺陷是TDP43核位置中断的上游 功能丧失，该途径可能不仅与ALS和FTD相关 - 而且其他神经系统损伤 涉及TDP43的错误调节。最后，在过去的十年中的研究表明，神经退行性 疾病不仅是神经元的疾病，而且神经胶质细胞也有助于病理生理。许多 研究在ALS和神经退行性中实现了异常的星形胶质功能。区域改变 长期以来已经知道了星形胶质细胞，但是这种情况是如何发生的，并且星形胶质细胞是否以功能/分子的形式存在 亚型尚不清楚。现在，我们小组和其他人的新研究提出了星形胶质细胞的真正亚型 存在，可能具有特定功能n调节皮质树突状和突触生物学，并且可以选择性地 在ALS中改变。这些新鉴定的亚组的生物学将在本提案中探讨 改变刺/树突，神经元元素在神经退行性中被动态改变。