Feedback amplification between Retrotransposons/endogenous retroviruses and TDP-43 in Alzheimers related dementias

阿尔茨海默病相关痴呆中逆转录转座子/内源性逆转录病毒和 TDP-43 之间的反馈放大

• 批准号: 10698169
• 负责人: JOSHUA T DUBNAU
• 金额: $ 77.91万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10698169
• 关键词: Age; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Amyotrophic Lateral Sclerosis; Astrocytes; Brain; Cell Culture Techniques; Cell Death; Cells; Clinical; Cultured Cells; DNA Damage; Data; Diagnosis; Disease; Disease Progression; Drosophila genus; Elements; Endogenous Retroviruses; Exhibits; Face; Feedback; Frontotemporal Dementia; Functional disorder; Genes; Genome; Human; Infection; Intervention; Literature; Mammalian Cell; Mediator; Modeling; Movement; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neurons; Onset of illness; Outcome; Pathology; Patients; Pharmaceutical Preparations; Physiological; Play; Publications; RNA Sequences; Reporter; Retrotransposon; Retroviridae; Risk; Role; Site; System; TDP-43 aggregation; Testing; Tissues; Virus; Work; age related; clinically relevant; design; experimental study; fly; frontotemporal lobar dementia amyotrophic lateral sclerosis; human subject; in vivo; insight; knock-down; neural; novel; perineural; protein TDP-43; protein aggregation; proteostasis; stem; success; transmission process

PROJECT ABSTRACT This proposal investigates a novel idea to explain how TDP-43 protein pathology is amplified and spread between glia and neurons after initiation of disease. TDP-43 aggregation pathology is a core feature of a suite of neurodegenerative disorders including frontotemporal dementia, Alzheimer’s and amyotrophic lateral sclerosis. We propose and will test the hypothesis that retrotransposons and endogenous retroviruses are both activated by TDP-43 pathology and can be upstream initiators of such pathology. We also will test the idea that these mobile elements contribute a mechanism of inter-cellular spread that could underlie progression of disease. We will use both Drosophila models and mammalian cell culture to test the core features of this proposed model.

项目摘要 该提案研究了一个新想法来解释 TDP-43 蛋白病理学的原理 疾病发生后，TDP-43 在神经胶质细胞和神经元之间扩增并传播。 聚集病理学是一系列神经退行性疾病的核心特征 包括额颞叶痴呆、阿尔茨海默病和肌萎缩侧索硬化症。 提出并将检验逆转录转座子和内源逆转录病毒的假设 两者均由 TDP-43 病理学激活，并且可以是此类疾病的上游启动子 我们还将测试这些移动元素贡献一种机制的想法。 我们将使用这两种方法来研究可能导致疾病进展的细胞间传播。 果蝇模型和哺乳动物细胞培养来测试该提议的核心特征 模型。