Contributors to FXTAS Progression

FXTAS 进步的贡献者

• 批准号: 10506703
• 负责人: CECILIA GIULIVI
• 金额: $ 43.93万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10506703
• 关键词: 5' Untranslated Regions; Affect; Age; Amyloidosis; Anxiety; Ataxia; Bioenergetics; Biological; Blood; CD36 gene; CGG repeat; CGG repeat expansion; Caliber; Cell Communication; Cell membrane; Cells; Clinical; Cognition; Data; Development; Diagnosis; Disease; Disease Progression; Energy Metabolism; Evaluation; FMR1; FMR1 Premutation; FXTAS; Family; Fragile X Syndrome; Funding; Genes; Genotype; Goals; Immune response; Inflammation; Inflammatory Response; Learning; Link; Location; Matched Group; Mediating; Mediator of activation protein; Membrane; Mental Depression; Metabolic; MicroRNAs; Microglia; Mitochondria; Molecular; Morbidity - disease rate; Morphology; Names; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neurons; Neuropsychology; Outcome; Oxidative Stress; Pathway interactions; Patients; Phenotype; Plasma; Process; Proteins; Proteomics; PubMed; RNA; Research; Research Subjects; Signal Transduction; Signal Transduction Pathway; Testing; Tissues; Toxic effect; Tremor; United States National Institutes of Health; Vesicle; base; cell type; cohort; eligible participant; exosome; extracellular; extracellular vesicles; genetic testing; high risk; insight; interest; mitochondrial dysfunction; nervous system disorder; neuroinflammation; neuronal metabolism; novel; prevent; protein profiling; recruit; response; sex

SUMMARY Carriers of the FMR1 premutation have expanded CGG repeats at the 5’ UTR of this gene. Carriers have a higher risk of developing fragile X-associated tremor/ataxia syndrome (FXTAS), a progressive neurodegenerative disease accompanied by tremor and ataxia as well as deficits in cognition, learning, and other neuropsychological issues (depression, anxiety). Neurodegeneration in FXTAS is accompanied by increased oxidative stress, lower mitochondrial bioenergetic capacity, limited unfolded protein response and a poorly characterized neuroinflammatory process. Surprisingly, not all carriers of the premutation develop FXTAS and the progression from milder to more detrimental stages is highly variable even in subjects with comparable age. As of today, there is no cure for FXTAS or to prevent its development. Exosomes are proposed to mediate pathophysiological signaling in a variety of target cells and their concentration spike in diseases associated with inflammation. Here, we hypothesize that circulating exosomes with detrimental cargoes are contributors to the onset and/or the progression of the disease. To this end, we will characterize exosomes from plasma obtained from sex- and age-matched noncarriers, carriers with and without FXTAS. The thorough characterization will entail evaluation of number and size, miRNA, and protein profiling. The characterization will serve as a platform to identify qualitative and quantitative differences as well as to identify the involvement of different biological pathways. The putative “toxic” effect of exosomes derived from carriers with and without FXTAS will be assessed by evaluating the bioenergetics of target cells (neurons and glia). These studies will provide an insight on the mechanism underlying the impact of exosomal components to the onset of mitochondrial dysfunction (as it is observed in carriers with FXTAS) and the progression of ataxia and tremors, key features of FXTAS-affected subjects.

概括 FMR1 预突变的携带者在该基因的 5' UTR 处扩展了 CGG 重复序列。 携带者患脆性 X 相关震颤/共济失调综合征 (FXTAS) 的风险较高， 一种进行性神经退行性疾病，伴有震颤、共济失调以及缺陷 认知、学习和其他神经心理学问题（抑郁、焦虑）。 FXTAS 中的神经退行性变伴随着氧化应激的增加、 线粒体生物能能力、有限的未折叠蛋白反应和较差的 特征性的神经炎症过程。令人惊讶的是，并非所有前突变携带者 发展 FXTAS 并且从较温和到更有害阶段的进展变化很大 即使在年龄相当的受试者中也是如此。截至目前，FXTAS 尚无治愈方法或预防方法 发展。外泌体被认为可以介导多种病理生理信号 与炎症相关的疾病中的靶细胞及其浓度峰值。在这里，我们 假设含有有害物质的循环外泌体是发病的原因 和/或疾病的进展。为此，我们将表征来自血浆的外泌体 从性别和年龄匹配的非携带者、有或没有 FXTAS 的携带者获得。这 全面的表征需要评估数量和大小、miRNA 和蛋白质 分析。表征将作为一个平台来识别定性和定量 差异以及确定不同生物途径的参与。假定的 来自带有和不带有 FXTAS 的载体的外泌体的“毒性”效应将通过 评估靶细胞（神经元和神经胶质细胞）的生物能学。这些研究将提供 深入了解外泌体成分对疾病发生影响的机制 线粒体功能障碍（在 FXTAS 携带者中观察到）和进展 共济失调和震颤是受 FXTAS 影响的受试者的主要特征。