GENETICS CORE

遗传学核心

基本信息

批准号：
7577453
负责人：
VIVIANNA M VAN DEERLIN
金额：
$ 25.46万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7577453
关键词：
Animal Disease Models Anterior Apolipoprotein E Biochemical Candidate Disease Gene Chromosomes, Human, Pair 17 Clinical Collection Communities Condition DNA Databases Dementia Diagnosis Disease Etiology Familial disease Family Family member Frontotemporal Dementia Functional disorder Generations Genes Genetic Genetic Counseling Genetic Research Genetic screening method Genotype Goals Individual Laboratories Language Lead Movement Disorders Mutation Mutation Analysis Nerve Degeneration Neurodegenerative Disorders Nucleic Acids Numbers Parkinsonian Disorders Patients Performance Personality Phenotype Presenile Dementia Program Research Project Grants RNA Research Resources Sampling Social Behavior Temporal Lobe Translating Translations alpha synuclein clinically relevant cohort executive function genetic analysis genetic pedigree kindred molecular pathology neuropathology novel presenilin-1 research study synuclein tau Proteins

项目摘要

Frontotemporal dementia (FTD) is a neurodegenerative disorder characterized clinically by changes in personality, social behavior, executive function, and/or language dysfunction, often in association with a movement disorder. The clinical manifestations of FTD are correlated with degeneration of the frontal and anterior temporal lobes. FTD can present either sporadically or as a familial disorder. Some of these kindred demonstrate an autosomal dominant pattem of inheritance. Elucidation of linkage to chromosome 17 and the subsequent identification of mutations in the tau gene (MAPT) in FTD cases provided direct evidence that tau protein dysfunction can lead to neurodegeneration. More than 30 different MAPT mutations have been identified. Studying familial forms of FTD can help elucidate the etiology and pathophysiology of FTD. Since FTDs are clinically heterogeneous, it is imperative to collect and study a large number of kindred to identify new mutations in MAPT and discover novel disease-associated genes. We began to collect DNA samples from individuals and families with FTD or related neurodegenerative disorders with the goal of enabling research genetic studies of such conditions. We now propose the formal establishment of a Genetics Core as a part of the Program Project Grant (PPG), Frontotemporal Dementias: Genotypes and Phenotypes to continue and expand this effort. The Genetics Core will provide genetic counseling to individuals and families with FTD and support the on-going collection and storage of DNA from these families. Limited genetic analysis of known genes associated with FTD will be performed to identify mutations. Finally clinically-relevant genetic tests will be translated to the clinical (CLIA-approved) laboratory. The collection of well-defined FTD cohorts and/or identification of new mutations will support genetic discoveries from Project 2, help advance the clinical characterization of FTD in Project 1, enable detailed biochemical and immunohistochemical analyses of FTD (Project 3), lead to the generation of new animal models of disease (Projects 2 & 4), and serve as a resource for genetic analysis of pathologically diagnosed cases of FTD in the Neuropathology Core to facilitate correlations between genotype and the clinical, neuropathological, and biochemical phenotypes.

额颞痴呆（FTD）是一种神经退行性障碍，其特征是人格，社会行为，执行功能和/或语言功能障碍的变化，通常与运动障碍相关。 FTD的临床表现与额叶和前颞叶的变性有关。 FTD可以偶尔出现或作为家庭疾病。这些亲属的一些表现出了遗传的常染色体主导奖。在FTD病例中阐明与17号染色体的连接以及随后识别Tau基因（MAPT）的突变提供了直接证据，表明TAU蛋白功能障碍会导致神经变性。已经确定了30多种不同的MAPT突变。研究FTD的家族形式可以帮助阐明FTD的病因和病理生理。由于FTD在临床上是异质的，因此必须收集和研究大量幼虫，以鉴定MAPT中的新突变并发现与疾病相关的新基因。我们开始从患有FTD或相关神经退行性疾病的个体和家庭中收集DNA样品，目的是实现对此类疾病的研究遗传研究。现在，我们建议将遗传学核心作为计划项目赠款（PPG）的一部分，额叶痴呆症：基因型和表型的一部分，以继续并扩大这一努力。遗传学核心将为具有FTD的个人和家庭提供遗传咨询，并支持这些家庭的DNA持续收集和存储。将对与FTD相关的已知基因进行有限的遗传分析以识别突变。最后，与临床相关的基因检测将转化为临床（CLIA批准）实验室。定义明确的FTD队列和/或识别新突变的收集将支持项目2中的遗传发现，有助于推进项目1中FTD的临床表征，使FTD的详细生化和免疫组织化学分析（项目3）（项目3）（项目3）（项目3），导致疾病的新动物模型的产生（探索2＆4）的生成（探索疾病的生成）。神经病理学的核心促进基因型与临床，神经病理学和生化表型之间的相关性。