TMEM230 and Neurodegeneration in Parkinson's Disease

TMEM230 与帕金森病的神经退行性变

基本信息

批准号：
10459555
负责人：
xugang xia
金额：
$ 34.66万
依托单位：
FLORIDA INTERNATIONAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-30 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10459555
关键词：
20p Affect Aging Animal Model Bioinformatics Biological Markers C-terminal Cell Culture Techniques Cell Death Cell physiology Chromosomes DNA Sequence Alteration Development Diagnosis Disease Disease Progression Dopamine Elderly Family Genes Genetic Genetic Polymorphism Genomics Human Immunoprecipitation Impairment Knock-in Knock-out Link Midbrain structure Molecular Molecular Chaperones Monitor Mutation Nature Nerve Degeneration Neurodegenerative Disorders Neurons Nucleotides Paper Parkinson Disease Pathogenesis Pathogenicity Pathologic Pathway interactions Patients Penetrance Phenotype Physiological Pilot Projects Point Mutation Process Proteins Proteomics Rattus Reporting Research Role Therapeutic Transgenic Organisms Variant cohort disease phenotype dopaminergic neuron effective therapy exome exome sequencing functional loss genetic linkage analysis genetic variant genome sequencing genome-wide linkage invention mutant neuron loss next generation sequencing novel overexpression promoter reuptake targeted sequencing therapeutic effectiveness tool whole genome

项目摘要

Parkinson’s disease (PD) is a common neurodegenerative disease characterized by progressive degeneration of dopaminergic neurons in the midbrain. At present, PD is incurable. A roadblock halting development of effective therapy for PD is the limited understanding of PD pathogenesis. While most PD cases are sporadic without an ascertained cause, about 10% of PD cases are likely caused by mutation of a known or unknown gene. Genetic clues not only help define the molecular pathways leading to neurodegeneration but also help identify biomarkers for monitoring disease progression and therapeutic effectiveness. Compared to the other neurodegenerative diseases, genetic discovery for PD is significantly deferred. One reason for deferred genetic discovery in PD is the incomplete penetrance of disease phenotypes in PD and it is particularly true for late-onset PD. A compelling need for PD research is identifying and validating the genes segregating with late-onset PD. Recently the new gene TMEM230 was reported to cosegregate with disease in a large family affected by late-onset PD. Once after a novel disease gene is identified, enormous efforts are required to validate the authenticity of the pathogenic role of the mutant gene in the disease. First, genetic variants cosegregating with the disease must be verified in independent families afflicted with the disease. Second, disease phenotypes observed in patients carrying the genetic variant must be reproduced in animal models expressing the disease-associated mutation. Third, mechanistic studies must be fulfilled to reveal how the disease-linked mutation impairs cellular functions and thus to determine how these new mechanisms are integrated into existing pathways leading to cell death in the disease. Validating process often takes many years to consolidate the authenticity of a genetic mutation after a disease gene is identified. In the proposed studies, we will take comprehensive approaches to validating the pathogenic role of TMEM230 mutation in late-onset PD by using both cell culture and animal models. Upon completion, our study will determine the effect of TMEM230 mutation on neuronal functions at both systemic and molecular levels.

帕金森氏病（PD）是一种以进行性变性为特征的常见神经退行性疾病中脑多巴胺能神经元。目前，PD无法治愈。障碍停止的发展 PD的有效治疗是对PD发病机理的有限理解。虽然大多数PD案例是零星的没有确定的原因，约有10％的PD病例可能是由于已知或未知的突变引起的基因。遗传簇不仅有助于定义导致神经变性的分子途径，而且还有助于确定生物标志物来监测疾病进展和治疗效果。与另一个神经退行性疾病，PD的遗传发现显着递延。递延遗传的原因之一 PD中的发现是PD疾病表型的不完全渗透性，对于晚发的PD尤其如此。对PD研究的迫切需求是识别和验证与晚期隔离的基因 PD。最近，据报道，新的基因TMEM230在一个受疾病的疾病中cosegractate 晚发的PD。一旦发现了一种新型疾病基因，就需要巨大的努力来验证突变基因在疾病中的致病作用的真实性。首先，遗传变异与必须在患有该疾病的独立家庭中验证该疾病。其次，疾病表型在表达与疾病相关的突变的动物模型中必须复制在携带遗传变异的患者中观察到的。第三，必须完全满足机械研究，以揭示疾病连接的突变损害细胞功能，从而确定如何将这些新机制集成到现有导致疾病细胞死亡的途径。验证过程通常需要多年才能合并鉴定出疾病基因后遗传突变的真实性。在拟议的研究中，我们将接受通过使用验证TMEM230突变在晚期PD中的致病作用的全面方法细胞培养和动物模型。完成后，我们的研究将确定TMEM230突变的效果关于全身和分子水平的神经元功能。