Contributors to FXTAS Progression

FXTAS 进步的贡献者

基本信息

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
项目类别：
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&apos 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

项目摘要

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 中的神经变性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令人惊讶的是，并非所有前突变携带者都具有神经炎症过程的特征。发展 FXTAS，从轻度到重度痛苦阶段的进展变化很大即使在年龄相当的受试者中，FXTAS 也无法治愈或预防。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。与货物一起循环的外泌体是发病的原因为此，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。全面的表征需要评估数量和大小、miRNA 和蛋白质特征分析将作为识别定性和定量的平台。差异以及确定不同生物途径的参与。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）的生物能学将提供一种方法。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。