Clinical and Translational Science Award

临床和转化科学奖

• 批准号: 9932779
• 负责人: Muredach P Reilly
• 金额: $ 63.99万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9932779
• 关键词: Abbreviations; Academic Medical Centers; Achievement; Adult; Age; Amyloid beta-Protein Precursor; Applications Grants; Astrocytes; Award; Chromosomes, Human, Pair 21; Clinical; Clinical Research; Clinical and Translational Science Awards; Collaborations; Communities; Consultations; Dental; Down Syndrome; Education; Educational Status; Ethics; Evolution; Faculty; Fibroblasts; Freedom; Funding; Genes; Gifts; Goals; Grant; Health Professional; Hospitals; Individual; Infrastructure; Inpatients; Institutes; Investigation; Knowledge; Laboratories; Left; Link; Medical center; Medicine; Methodology; Mission; National Center for Research Resources; Neurons; New York; Nursing Research; Organoids; Outpatients; Participant; Phenotype; Physicians; Population; Presbyterian Church; Privacy; Provider; Public Health Schools; Recording of previous events; Research; Research Personnel; Research Support; Resources; Role; Sampling; School Nursing; Scientist; Source; Structure; Students; Surgeon; Testing; Text; Time; Tissue-Specific Gene Expression; Training; Translational Research; Trustees; United States National Institutes of Health; Universities; Variant; Vision; Washington; base; biobank; college; cost; functional genomics; induced pluripotent stem cell; innovation; insight; multidisciplinary; neuron development; neuropathology; novel; outpatient facility; overexpression; programs; resilience; skills; three dimensional cell culture; tool; transcriptomics; web site

Due to triplication and overexpression of the gene for amyloid precursor protein and other genes on chromosome 21, individuals with Down Syndrome (DS) show neuropathologies of AD at an earlier age than the typical population, and about half of adults with DS develop AD. Yet there is wide phenotypic variation in adults with DS and many do not develop AD. This study proposes to use previously biobanked samples towards identifying factors that contribute to resilience to AD in adults with DS. The project will reprogram established fibroblast lines from older DS subjects with and without concomitant AD into induced pluripotent stem cells (iPSCs) and then differentiate these iPSCs into neurons and then into cortical organoids (mixed cortical neuron and astrocyte 3D culture). These organoids will be used to perform transcriptomic analysis and to examine differences in neuronal development and function. Specifically, this project will use a subset of the biobanked samples that examined over 500 adults with DS longitudinally to investigate DS-AD. We will: (1) reprogram established fibroblasts lines from older DS subjects with or without DS-AD into iPSCs, and then use these iPSCs to investigate: (1) the effects of neuronal development on DS-AD; (2) differential gene expressions and eQTL; and (3) the role of a novel gene, WWOX, in DS-AD. This study will generate resources that will enable researchers to perform functional genomic studies following identification of protective and putative genes in DS-AD.

由于 21 号染色体上淀粉样蛋白前体蛋白基因和其他基因的三重复制和过度表达，患有唐氏综合症 (DS) 的个体比典型人群更早地表现出 AD 神经病理学症状，大约一半患有 DS 的成年人会患上 AD。然而，患有 DS 的成年人存在广泛的表型变异，并且许多人不会发展为 AD。本研究建议使用之前生物库中的样本来确定有助于 DS 成人抵抗 AD 的因素。该项目将把患有或不患有 AD 的老年 DS 受试者的成纤维细胞系重新编程为诱导多能干细胞 (iPSC)，然后将这些 iPSC 分化为神经元，然后分化为皮质类器官（混合皮质神经元和星形胶质细胞 3D 培养物）。这些类器官将用于进行转录组分析并检查神经元发育和功能的差异。 具体来说，该项目将使用生物库样本的一个子集来研究 DS-AD，这些样本对 500 多名患有 DS 的成年人进行了纵向检查。我们将：（1）将患有或不患有 DS-AD 的老年 DS 受试者建立的成纤维细胞系重新编程为 iPSC，然后使用这些 iPSC 来研究：（1）神经元发育对 DS-AD 的影响； (2)差异基因表达和eQTL； (3) 一个新基因 WWOX 在 DS-AD 中的作用。这项研究将产生资源，使研究人员能够在鉴定 DS-AD 中的保护性和推定基因后进行功能基因组研究。