GENETICS CORE

项目总结： 额颞叶变性(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通常是家族性的，可作为一种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病理生理学，为治疗提供靶点，并识别改变疾病风险或表型的危险因素。为了能够进行FTLD的遗传学研究，Genetics Core将收集患有FTLD的临床核心B患者、具有神经病理核心特征的尸检大脑以及对照样本的DNA，并将其储存在该计划项目赠款中。对于参与的个人，一名接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的数据相关联，并由生物统计和数据管理核心进行统计分析。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，遗传学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 degeneration (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 frequently 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 mutations 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 genetic 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 participating individuals, a study coordinator trained as a certified genetic counselor will provide genetic education 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 will be performed by the Core and in collaboration with Project 1. Genotype data will enable clinical, pathologic and genetic correlations with data from Projects 1 and 3 and the Clinical and Neuropathology Cores with statistical analysis by the Biostatistics and Data Management Core. Projects 2 and 4 will use genotype data for case selection for analysis. Finally, the Genetics 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 translation into clinical tests and assist with validation by providing primer sequences, protocols, and samples