GENETICS CORE

项目概要： 额颞叶变性（FTLD）临床表现为进行性行为和/或语言缺陷。FTLD的亚型在神经病理学上通过细胞包涵体的蛋白质组成来分类。FTLD最常见的神经病理学相关物具有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疾病发生。具有引起FTLD的突变的基因包括/W/APT（编码tau）和GRN（编码颗粒蛋白前体）等，其中每一种都与特定的FTLD病理亚型相关：GRN突变与FTLD-TDP和MAPT突变与FTLD-tau。研究FTLD的遗传学有助于阐明其病因， 病理生理学和提供治疗靶点以及鉴定改变疾病风险或表型的风险因素。为了能够进行FTLD的遗传学研究，遗传学核心作为本计划项目资助的一个组成部分，将收集并储存来自临床核心B受试者的DNA，FTLD和神经病理学核心中表征的尸检大脑以及对照样本。对于参与研究的个人，经过认证的遗传咨询师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。库DNA将用于核心本身的遗传分析，以及项目1，和其他合作者内外的宾夕法尼亚大学。FTLD相关基因的遗传分析将由核心小组与项目1合作进行。基因型数据将使临床、病理学和遗传学与项目1和3的数据以及临床和神经病理学核心数据相关联，并由生物统计学和数据管理核心进行统计分析。项目2和项目4将使用基因型数据进行病例选择分析。 最后，Genefics Core将与宾夕法尼亚大学分子病理学实验室的医院协调，提供CLIA认证的基因检测。为此，核心将确定新的基因测试，准备进入临床测试，并通过提供引物序列，协议和样本来协助验证。

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.