South Texas Alzheimer's Disease Center Genetics and Multiomics Core

南德克萨斯阿尔茨海默病中心遗传学和多组学核心

基本信息

批准号：
10270731
负责人：
Sudha Seshadri
金额：
$ 25.68万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10270731
关键词：
ATAC-seq Address Affect African American Aging Alzheimer&apos s Disease Alzheimer&apos s disease related dementia Amyloid Area Astrocytes Biological Biological Markers Biology Blood Brain Cells Cholesterol Clinical Clinical Trials Collaborations Communities Comprehensive Health Care Consensus Consent DNA DNA Sequence Alteration Data Data Analyses Data Set Dementia Diagnosis Disease Disease Progression Diverse Workforce Elderly Eligibility Determination Endowment Enrollment Ensure Ethics Extended Family Faculty Family Family history of First Degree Relative Funding Genes Genetic Genetic Counseling Genetic Diseases Genetic Risk Genetic Variation Genomics Genotype Goals Grant Heart Heterogeneity Hispanic Americans Hispanics Individual Inflammation International Lead Magnetic Resonance Imaging Medical Medical Genetics Methods Methylation Mexican Americans Microglia Mitochondria Motor Multiomic Data Mutation Neurons Neurosciences Not Hispanic or Latino Nuclear Pore Complex Office of Administrative Management Oligodendroglia Organoids Participant Pathologic Pathway interactions Patients Pharmaceutical Preparations Phenotype Population Population Heterogeneity Positron-Emission Tomography Precision therapeutics Prevention Research Research Methodology Research Personnel Research Support Resources Risk Risk Estimate Sampling Science Sensory Serum South Texas Syndrome Training Training Programs Validation Work biobank catalyst cell type clinical sequencing cohort data management digital education research follow-up functional genomics genetic association genetic variant genome sequencing genome wide association study genomic data genomic epidemiology graduate student imaging biomarker improved individual patient individualized prevention induced pluripotent stem cell innovation lipidomics machine learning method member metabolomics multiple omics neuropathology new therapeutic target normal aging novel personalized medicine phenotypic data precision medicine proband prognostic ranpirnase recruit resilience risk stratification symposium tau Proteins therapeutic target transcriptomics whole genome

项目摘要

Dementia in older adults is clinically, genetically and pathologically heterogeneous. Understanding this heterogeneity and addressing all the biological pathways that increase risk and lower resilience, will be required to provide precision prevention, diagnosis and treatment. Genome wide association studies (GWAS) have implicated over 40 genes, multiple cell and varied biological pathways (amyloid, tau, endolysosomal, mitochondrial function, inflammation). Genetic and multiomic characterization of ADRD in individuals, and in groups of patients, could exploit this heterogeneity towards more effective, precise, personalized prevention and treatment of dementia. Whereas, most of these biological discoveries have been in non-Hispanic whites, there is a paucity of data on Mexican American (MA) Hispanics, who are the fastest growing segment of older adults in the US. The Genetics and Multiomics Core (GMC) of the South Texas Alzheimer Disease Consortium (STAC) has the following specific aims: Aim 1: Identifying causal genetic variation underlying ADRD in CC enrollees through a combination of routine clinical sequencing and a ‘Undiagnosed Disease Network’ approach to identifying novel genetic variation that may be causal or contributory. To achieve this, we will record results of clinical sequencing and genetic counseling in proband and relatives. Aim 2: Genetically characterize all CC enrollees (using APOE and GWAS) to expand our understanding of genetic variation modifying risk, resilience and disease progression. We will aim to refine and improve genetic risk estimates for late onset AD, PD, DLB permitting more accurate risk stratification in MA Hispanics, better targeting for recruitment in clinical trials. Aim 3: Serve as a resource for STAC investigators, trainees, and the national ADRD research community for deeply phenotyped Hispanic MA samples, genomic data and innovative analysis methods. To achieve this (i) GMC will share DNA, genetic and phenotypic data (clinical, MRI and PET imaging, blood and CSF -amyloid, tau, inflammation, metabolomic, lipidomic- and sensory-motor biomarkers) and digital and conventional neuropathology, through NCRAD, NIAGADS, NACC; (ii) GMC will serve as a STAC resource for providing methylation, transcriptomics (blood, brain, CSF), ATAC-Seq, single-cell omics data and for generating usable iPSCs and organoids; (iii) GMC will develop and share innovative genetic and multiomic association analyses methods, especially for use in large families; (iv) GMC will facilitate collaborations with consortia such as the Alzheimer Disease Genetics Consortium (ADGC), the International Genomics of AD Project (IGAP), Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) and Transomics in Precision Medicine (TOPMed); (v) GMC faculty and resources will support the Research Education Core in developing a diverse workforce, well-trained in applying genetic and multiomic research methods.

老年人痴呆症在临床、遗传和病理学上具有异质性。异质性并解决所有增加风险和降低复原力的生物途径，将是需要提供精准的预防、诊断和治疗。涉及 40 多个基因、多个细胞和不同的生物途径（淀粉样蛋白、tau、内溶酶体、线粒体功能、炎症）。ADRD 在个体中的遗传和多组学特征。患者群体可以利用这种异质性来实现更有效、精确、个性化的预防和痴呆症的治疗，除了这些生物学发现大部分是在非西班牙裔白人身上，关于墨西哥裔美国人 (MA) 西班牙裔的数据很少，他们是老年人中增长最快的群体美国成年人的南德克萨斯阿尔茨海默病的遗传学和多组学核心 (GMC)。联盟（STAC）有以下具体目标：目标 1：通过结合以下方法来识别 CC 参与者中 ADRD 的因果遗传变异常规临床测序和“未确诊疾病网络”方法来识别新基因为了实现这一目标，我们将记录临床测序和结果。先证者及其亲属的遗传咨询。目标 2：对所有 CC 参与者进行基因表征（使用 APOE 和 GWAS）以扩展我们的研究我们的目标是完善对遗传变异改变风险、恢复力和疾病进展的理解。改善迟发性 AD、PD、DLB 的遗传风险估计，从而可以更准确地进行风险分层 MA 西班牙裔，更好地针对临床试验招募。目标 3：为 STAC 研究人员、学员和国家 ADRD 研究提供资源深度表型西班牙裔 MA 样本、基因组数据和创新分析方法的社区。为了实现这一目标 (i) GMC 将共享 DNA、遗传和表型数据（临床、MRI 和 PET 成像、血液和脑脊液（淀粉样蛋白、tau蛋白、炎症、代谢组学、脂质组学和感觉运动生物标志物）和数字和传统神经病理学，通过 NCRAD、NIAGADS、NACC；(ii) GMC 将充当 STAC；提供甲基化、转录组学（血液、大脑、CSF）、ATAC-Seq、单细胞组学数据和用于生成可用的 iPSC 和类器官；(iii) GMC 将开发和分享创新的遗传和多组学 (iv) GMC 将促进与联盟，例如阿尔茨海默病遗传学联盟 (ADGC)、国际 AD 基因组学联盟项目 (IGAP)、基因组流行病学心脏和衰老研究队列 (CHARGE) 和跨组学精准医学 (TOPMed)；(v) GMC 师资和资源将支持以下领域的研究教育核心：培养一支多元化的劳动力队伍，在应用遗传和多组学研究方法方面接受过良好的培训。