Dominantly Inherited Alzheimer Network: Genetics Core

显性遗传阿尔茨海默病网络：遗传学核心

基本信息

批准号：
10017835
负责人：
Carlos Cruchaga
金额：
$ 31.45万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-15 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10017835
关键词：
Advisory Committees Age Alzheimer&apos s Disease Alzheimer’s disease biomarker Amyloid beta-Protein Amyloid deposition Basic Science Biocompatible Materials Biological Biological Markers Biostatistics Core Blood Blood specimen Brain CRISPR/Cas technology Cell Line Cells Clinical Clinical Sciences Clinical Trials Clinical assessments Cognitive Collection Communities DNA DNA Library DNA Methylation DNA Sequence Alteration Data Data Collection Databases Dermal Development Diagnosis Disease Disease Progression Enrollment Ethnic Origin Event Exons Family Fibroblasts Freezing Funding Future Genes Genetic Genetic Databases Genetic Fingerprintings Genetic Markers Genetic Variation Genomics Genotype Goals Human Resources Image Impairment Individual Inflammation Inherited Investigation Letters Leukocytes Life Style Longitudinal Studies Measurement Molecular Mutation Natural History Observational Study Onset of illness Participant Pathogenesis Pathogenicity Phase Phenotype Positron-Emission Tomography Protocols documentation Psychometrics Quality Control RNA Rare Diseases Reproducibility Research Research Personnel Resources Risk Sampling Series Ships Site Somatic Cell Technology Telephone Testing Treatment Efficacy Tube United States National Institutes of Health Variant Visit Work alpha synuclein base behavioral study cell repository disease-causing mutation early onset efficacy testing endophenotype follow-up genetic information genome editing genome wide association study genomic data high standard induced pluripotent stem cell insight kindred longitudinal analysis mutational status neuroimaging marker novel novel marker novel therapeutics outcome forecast phenome polygenic risk score pre-clinical recruit regional atrophy stem cells symposium tau Proteins therapeutic evaluation transcriptomics

项目摘要

Core F: Genetics SUMMARY During the last two decades three genes have been shown to cause autosomal dominant forms of early onset dementing illnesses. These rare disorders have provided enormous insight into the pathogenesis of more common variants of the same diseases. Several of the most promising new therapeutics are based on the Aß hypothesis, a hypothesis strongly supported by the causative mechanisms of disease mutations in autosomal dominant families. As these putative therapeutics are tested in clinical trials there is a growing need to use the ADAD kindreds both to understand the natural history of the earliest clinical and preclinical phases of the disease and to test the efficacy of the therapeutics in a setting, where if the Aβ hypothesis is correct, they should have a dramatic effect on prognosis. During the last funding cycle, we have expanded our network of centers and have begun longitudinal characterization of a large series of ADAD kindreds with known disease-causing mutations. The goal of the next funding period will be to continue longitudinal follow up of these kindreds to identify the earliest detectable changes associated with development of disease and to characterize the temporal series of events that occurs up to and including the diagnosis of symptomatic AD. The goal of the Genetics Core of the DIAN initiative is to provide genetic information and useful biological and genomic materials to the research community for the study of AD. We have already collected genomic samples from 531 individuals and generated fibroblasts from 99 individuals. We anticipate collection of an additional 125 new individuals during the next funding cycle, including participants from NIH and self-funded sites. We will expand the fibroblast and induced pluripotent stem cell collection. The Core will maintain and curate a list of pathogenic mutations and confirm that new DIAN families carry an ADAD mutation. The Core will also generate GWAS and APOE genotype data on all individuals and obtain biological materials (fibroblasts, induced pluripotent stem cells, white blood cells) to perform cell-based functional studies. All data will be placed in the DIAN database. We will support all projects in DIAN and perform analyses with other Cores to identify novel factors modulating age at onset in these families.

核心F：遗传学摘要在过去的二十年中痴呆疾病。这些罕见的疾病为更多的发病机理提供了巨大的见解相同疾病的常见变体。几种最有希望的新疗法是基于Aß 假设，一个假设由常染色体突变的灾难性机制支持主导家庭。由于这些推定的治疗剂在临床试验中进行了测试，因此使用越来越多的需要阿德德（Adad 并在某种程度上测试治疗疗法的效率，如果Aβ假设正确，则应具有对预后的戏剧性影响。在上一个融资周期中，我们扩展了我们的中心网络，并拥有一系列具有已知疾病突变的ADAD犬种的纵向表征。下一个资金期的目标将是继续对这些亲戚的纵向跟进，以确定与疾病发展相关的最早可检测的变化，并表征临时系列发生的事件和包括症状广告的诊断。遗传学核心的目标 Dian倡议是为研究提供遗传信息以及有用的生物学和基因组材料广告研究的社区。我们已经收集了来自531个个体的基因组样本并生成来自99个个体的成纤维细胞。我们预计在下一个期间会收集另外125个新人资金周期，包括来自NIH和自筹资金站点的参与者。我们将扩展成纤维细胞并诱导多能干细胞收集。核心将维护并策划病原突变的列表，并确认新黛安家庭带有ADAD突变。核心还将生成GWAS和APOE基因型数据所有个体并获得生物材料（成纤维细胞，诱导多能干细胞，白细胞）进行基于细胞的功能研究。所有数据都将放置在Dian数据库中。我们将支持所有项目在Dian并与其他核心进行分析，以确定这些家族发病年龄调节年龄的新因素。