Identification of pathogenic mechanisms important in multiple system atrophy

鉴定多系统萎缩中重要的致病机制

基本信息

批准号：
8955003
负责人：
Matt Huentelman
金额：
$ 40.36万
依托单位：
TRANSLATIONAL GENOMICS RESEARCH INST
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8955003
关键词：
Adult Affect Age of Onset Applications Grants Area Automobile Driving Autonomic Dysfunction Belief Biological Process Brain Calcium Cell Culture Techniques Cell Line Cells Cerebellum Characteristics Childhood Clustered Regularly Interspaced Short Palindromic Repeats Corpus striatum structure Coupled Cytoplasmic Inclusion Data Defect Development Diagnosis Disabled Persons Disease Disease Progression Dopamine Engineered Gene Engineering Environmental Risk Factor Etiology FYN gene Family Family Study Frequencies Future Gene Transfer Genes Genetic Genomics Gliosis Goals Health Homeostasis Human Immunohistochemistry In Vitro Institutes Intervention Investigation LRRK2 gene Lewy Body Dementia Light Mean Survival Times Motor Multiple System Atrophy Mutation Nerve Degeneration Neurodegenerative Disorders Neurologic Neurons Nuclear Family Oligodendroglia Parents Parkinson Disease Parkinsonian Disorders Pathology Pathway interactions Patients Population Process Rare Diseases Research Research Institute Risk Role Severity of illness Siblings Specimen Spinal Cord Column Substantia nigra structure Symptoms Testing The Sun Therapeutic Tissue Banking Tissue Banks Tissues Validation Variant alpha synuclein base brain tissue calcium metabolism case control design differential expression dopamine transporter exome sequencing follow-up genetic variant genome sequencing interest laser capture microdissection lens middle age mutant nervous system disorder neuron loss neurotransmission next generation next generation sequencing prevent public health relevance research study synucleinopathy targeted treatment therapeutic target transcriptome sequencing tumor white matter

项目摘要

DESCRIPTION (provided by applicant): There are many examples where the study of rare disease has fundamentally changed our understanding of common diseases with similar phenotypic characteristics. This is true to a large extent because the rare disease represents a much clearer "lens" by which to understand the mechanisms of the disorder. This grant proposal focuses on the investigation of multiple system atrophy (MSA), a rare but severe neurodegenerative synucleinopathy with adult onset characterized by autonomic dysfunction with parkinsonism and/or cerebellar symptoms. Of specific interest in MSA are the oligodendroglial and neuronal cytoplasmic inclusions (GCIs and NCIs) formed by fibrillar alpha-synuclein (a-SYN) proteins although the pathogenic mechanisms driving these accumulations are unclear. Currently, there are no disease preventing or modifying treatments for MSA, and a crucial need for research to identify pathways that can be targeted for therapy. Little research has been done to understand the etiology of this disease especially in the area of modern genomic sequencing even though such an approach has revolutionized the way rare childhood disorders are investigated. Our first goal is to use family-based genomics to uncover rare genetic variants associated with MSA. We will perform genomic sequencing on quads of MSA patients, parents, and one unaffected sibling. Identified genetic variants will be characterized in vitro by using CRISPR-Cas9 engineering of existing cell-lines. Our second goal is to identify the pathogenic mechanisms important to MSA a-SYN accumulation, by combining laser capture microdissection and next generation RNA-Seq in neuropath-confirmed MSA brains and matched controls. Both of these aims are designed to identify underlying disease mechanisms and key targets that could be exploited as potential future therapeutic options. Our findings may shed additional light on the mechanisms of disease in more common synucleinopathies like Parkinson's disease and Lewy Body Dementia.

描述（由适用提供）：在许多例子中，对罕见疾病的研究从根本上改变了我们对具有相似表型特征的常见疾病的理解。这在很大程度上是如此，因为罕见疾病代表了一种更清晰的“镜头”，可以理解该疾病的机制。该赠款提案的重点是对多系统萎缩（MSA）的研究，这是一种罕见但严重的神经退行性突触性核酸，具有成人发作，其特征在于帕金森氏症和/或小脑症状。在MSA中特别感兴趣的是纤维胶质和神经元细胞质内包含物（GCIS和NCIS）由Fibrillar alpha-synclein（A-Synn）蛋白形成的，尽管尚不清楚驱动这些积累的致病机制尚不清楚。当前，没有疾病可以预防或修改MSA治疗，并且至关重要的需要研究以识别可以针对治疗的途径。几乎没有研究了解这种疾病的病因，尤其是在现代基因组测序领域，尽管这种方法彻底改变了罕见的儿童疾病的研究方式。我们的第一个目标是使用基于家庭的基因组学来发现与MSA相关的稀有遗传变异。我们将对MSA患者，父母和一个未受影响的兄弟姐妹的四足动物进行基因组测序。确定的遗传变异将在通过使用现有细胞线的CRISPR-CAS9工程进行体外。我们的第二个目标是通过将激光捕获的微分辨率和下一代RNA-SEQ结合在神经病患者固定的MSA大脑和匹配的对照中来确定对MSA A-SYN积累重要的致病机制。这两种目标均旨在识别潜在的疾病机制和可能被利用的未来治疗选择的关键靶标。我们的发现可能会详细介绍帕金森氏病和刘易体内痴呆等更常见的突触性核酸疾病的疾病机制。