Genetics Core

遗传学核心

• 批准号: 8999440
• 负责人: VIVIANNA M VAN DEERLIN
• 金额: $ 22.53万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 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/8999440
• 关键词: Affect; Archives; Autopsy; Behavioral; Biological Markers; Biometry; Brain; C9ORF72; Clinical; Clinical Trials; Collaborations; Communities; Counseling; Custom; DNA; DNA Library; DNA Sequence Alteration; DNA-Binding Proteins; Data; Data Correlations; Databases; Diagnosis; Disease; Disease Progression; Education; Educational Materials; Etiology; Evaluation; Exclusion; Family; Family member; Fostering; Frontotemporal Dementia; Frontotemporal Lobar Degenerations; Functional disorder; Genes; Genetic; Genetic study; Genome; Genomics; Genotype; Goals; Grant; Haplotypes; Health Insurance Portability and Accountability Act; Inclusion Bodies; Informed Consent; Inherited; International; Language Disorders; Methods; Mutation; Neurodegenerative Disorders; Nucleic Acids; Participant; Pathologic; Pathology; Patients; Pennsylvania; Phenotype; Pick Disease of the Brain; Process; Program Research Project Grants; Progress Reports; Progressive Supranuclear Palsy; Proteins; Publications; RNA; Recording of previous events; Research; Research Personnel; Resources; Risk Factors; Sampling; Single Nucleotide Polymorphism; Statistical Data Interpretation; Testing; Text; Universities; Update; Variant; abstracting; cohort; corticobasal degeneration; data management; disorder risk; endophenotype; exome; follow-up; frontotemporal degeneration; genetic analysis; genetic information; genetic pedigree; genetic risk factor; genome analysis; genotyped patients; imaging biomarker; interest; mutation screening; neuropathology; next generation sequencing; personalized medicine; prevent; protein TDP-43; protein aggregation; risk variant; targeted treatment; tau Proteins; therapeutic development; variant of unknown significance

Genetics Core: Project Summary/Abstract Genetics Core C of the competing renewal of this Program Project Grant (PPG) entitled “Frontotemporal Dementias: Genotypes and Phenotypes” aims to continue to build a large well-characterized cohort of DNA samples, and use and share these samples for cutting-edge genomic applications to foster new genetic discoveries within and beyond this PPG, which seeks to advance understanding of mechanisms underlying the onset and progression of hereditary and sporadic forms of frontotemporal degeneration (FTD). FTD manifests clinically with progressive behavioral and/or language deficits with subtypes classified neuropathologically by the different disease proteins found as cellular inclusion bodies, of which the most common are TAR DNA binding protein (TDP-43, FTLD-TDP) and tau (FTLD-tau). Autosomal dominant forms of FTD have been identified with mutations most commonly in MAPT, GRN, and C9orf72, and each is associated with a specific FTLD pathological subtype, for example, GRN and C9orf72 mutations with FTLD-TDP and MAPT mutations with FTLD-tau. In addition, genetic risk factors, such as TMEM106B, have been identified. Studying the genetics of FTD can help to elucidate its etiology and pathophysiology as well as identify genetic factors that increase risk for disease or modify its phenotype. New evidence for protein aggregation and spread throughout the CNS in FTD and other NDs (studied in Projects 3 and 4) provides a promising target for therapeutic development for these currently incurable disorders. However, accurate, as well as rapid, ante mortem diagnosis of FTD underlying pathology is crucial for this effort. A personalized medicine approach that combines genetic information with other biomarkers (imaging, biofluids) to better define FTD clinical endophenotypes will enhance power for clinical trials focused on slowing or preventing progression of spread of tau, TDP-43 and other FTLD-associated pathologies. To enable genetic studies of FTD in this PPG, Core C will collect and bank DNA from Clinical Core B subjects and autopsy brains characterized in Neuropathology and Biomarker Core D. DNA will be used for genetic analysis by Core C and Project 2 and be available to share with other collaborators. Genetic mutations and SNP risk factor data, will be used by Project 1 to assess factors contributing to rate of disease progression. Genotype data will enable selection of cases (either inclusion or exclusion of cases with a mutation, for example) for study in Projects 1-4. In addition, genetic data will enable clinical, pathologic and genetic correlations with data from Projects 1-4 and Cores B and D. Biostatistics and Data Management Core E will perform statistical analysis for these studies. Genomic analysis at the exome and genome level will be used to identify new genes in families without an identified mutation and for additional genomic association studies both within this PPG and in local, national, and international collaborations under the guidance of Administrative Core A.

遗传学核心：项目摘要/摘要 该计划项目赠款（PPG）竞争更新的遗传学核心C，题为“额颞 痴呆症：基因型和表型”的目的是继续建立大型良好的DNA群体 样品，并使用并共享这些样品用于尖端的基因组应用来促进新的遗传 该PPG内外的发现，旨在提高人们对依据的机制的理解 纹状体变性（FTD）的遗传和零星形式的发作和进展。 FTD表现出来 临床上的行为行为和/或语言在神经病理学上定义了通过 发现的不同疾病蛋白作为细胞包容体，其中最常见的是焦油DNA 结合蛋白（TDP-43，FTLD-TDP）和TAU（FTLD-TAU）。 FTD的常染色体主导形式已经 在MAPT，GRN和C9ORF72中最常见的突变鉴定，并且每个突变都与特定的 FTLD病理亚型，例如，使用FTLD-TDP和MAPT突变的GRN和C9ORF72突变 与ftld-tau。此外，已经确定了遗传危险因素，例如TMEM106B。研究 FTD的遗传学可以帮助阐明其病因和病理生理学，并确定遗传因素 增加疾病的风险或改变其表型。蛋白质聚集的新证据并分布在整个 FTD和其他ND的中枢神经系统（项目3和4中的研究）为治疗提供了有希望的目标 这些目前无法治愈的疾病的发展。但是，准确且快速的ante mortem FTD基础病理学的诊断对于这项工作至关重要。一种个性化医学方法 将遗传信息与其他生物标志物（成像，生物流体）结合起来，以更好地定义FTD临床 内型型将增强临床试验的功率，该试验侧重于放缓或预防传播的发展 Tau，TDP-43和其他与FTLD相关的病理。为了在此PPG中启用FTD的遗传研究 将从临床核心B受试者和尸检中收集和银行DNA。 和生物标志物核心D. DNA将用于Core C和Project 2的遗传分析，可用于 与其他合作者分享。项目1将使用基因突变和SNP风险因素数据来评估 导致疾病进展率的因素。基因型数据将可以选择病例（要么 例如，在项目1-4中进行研究，包括或排除具有突变的病例）。另外，遗传数据 将与项目1-4和核心B和D的数据实现临床，病理和遗传相关性。 生物统计学和数据管理核心E将对这些研究进行统计分析。基因组分析 在外部和基因组水平上，将用于识别未识别突变和的家庭中的新基因 在该PPG和本地，国家和国际的其他基因组协会研究中 在行政核心A的指导下进行的合作。