GENETICS CORE

项目总结： 额颞叶退行性变(FTLD)临床表现为进行性行为和/或语言障碍。FTLD的亚型根据细胞包涵体的蛋白质组成进行神经病理学分类。与FTLD相关的最常见的神经病理因素有TAR DNA结合蛋白(TDP-43)、包涵体(FTLD-TDP)或tau包涵体(FTLD-tau)。FTLD是常见的家族性疾病，可作为常染色体显性遗传性疾病发生。导致FTLD的突变基因包括/W/apt(编码tau)和grn(编码原颗粒蛋白)等，每一种突变都与FTLD病理亚型有关：FTLD-TDP的GRN突变和FTLD-tau的MAPT突变。研究FTLD的遗传学有助于阐明其病因和发病机制。 病理生理学，并提供治疗的目标，以及确定改变疾病风险或表型的风险因素。为了能够对FTLD进行基因组学研究，Genetics Core将收集和储存患有FTLD的临床核心B患者、以神经病理学核心为特征的尸检大脑以及对照样本的DNA，作为该计划项目拨款的一个组成部分。对于参与的个人，一名受过认证遗传顾问培训的研究协调员将提供遗传教育，以促进对研究的更好理解，并获得知情同意。储存的DNA将被核心项目本身以及项目1和宾夕法尼亚大学内外的其他合作者用于基因分析。FTLD相关基因的遗传分析将由核心进行，并与项目1合作进行。基因数据将使临床、病理和遗传与项目1和3的数据以及临床和神经病理核心与生物统计和数据管理核心的统计分析相关联。项目2和项目4将使用基因数据进行病例选择和分析。 最后，基因核心将与大学医院协调。宾夕法尼亚分子病理学实验室提供CLIA认证的基因测试。为此，核心将确定新的基因测试，准备将其转化为临床测试，并通过提供引物序列、方案和样本来协助验证

PROJECT SUMMARY: Frontotemporal Lobar degenerafion (FTLD) manifests clinically with progressive behavioral and/or language deficits. Subtypes of FTLD are classified neuropathologically by the protein composition of cellular inclusion bodies. The most common neuropathological correlates of FTLD have TAR DNA binding protein (TDP-43) inclusions (FTLD-TDP) or tau inclusions (FTLD-tau). FTLD is frequenfiy familial and can occur as an autosomal dominantly inherited disorder. Genes with mutations causing FTLD include /W/APT (encodes tau) and GRN (encodes progranulin) among others, each of which is associated with a specific FTLD pathological subtype: GRN mutations with FTLD-TDP and MAPT mutafions with FTLD-tau. Studying the genetics of FTLD can help elucidate its etiology and pathophysiology and provide targets for therapy as well as identify risk factors that modify disease risk or phenotype. To enable genefic studies of FTLD the Genetics Core, as an integral part of this Program Project Grant, will collect and bank DNA from Clinical Core B subjects with FTLD and autopsy brains characterized in the Neuropathology Core as well as control samples. For participafing individuals, a study coordinator trained as a certified genetic counselor will provide genetic educafion to foster a better understanding of the research and to obtain informed consent. Banked DNA will be used for genetic analysis by the Core itself, as well as by Project 1, and other collaborators within and outside of UPenn. Genetic analysis of FTLD associated genes willbe performed by the Core and in collaboration with Project 1. Genotype data will enable clinical, pathologic and genetic correlafions with data from Projects 1 and 3 and the Clinical and Neuropathology Cores with stafisfical analysis by the Biostatistics and Data Management Core. Projects 2 and 4 will use genotype data for case selection for analysis. Finally, the Genefics Core will coordinate with the Hosp. of the Univ. of Penn Molecular Pathology Lab to make CLIA-certified genetic testing available. To this end, the Core will identify new genetic tests which are ready for translafion into clinical tests and assist with validation by providing primer sequences, protocols, and samples