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号染色体上淀粉样前体蛋白基因和其他基因的三倍和过表达，唐氏综合征（DS）患者在比典型人群更早的年龄显示出AD的神经病理学，并且大约一半的DS成人发展为AD。然而，在DS成人中存在广泛的表型变异，许多人不会发展为AD。本研究建议使用以前的生物库样本，以确定有助于DS成人对AD恢复力的因素。该项目将从患有和不患有伴随AD的老年DS受试者中建立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）。这些类器官将用于进行转录组学分析，并检查神经元发育和功能的差异。 具体而言，该项目将使用生物库样本的一个子集，纵向检查超过500名患有DS的成年人，以调查DS-AD。我们将：（1）将来自患有或不患有DS-AD的老年DS受试者的已建立的成纤维细胞系重新编程为iPSC，然后使用这些iPSC研究：（1）神经元发育对DS-AD的影响;（2）差异基因表达和eQTL;以及（3）新基因WWOX在DS-AD中的作用。这项研究将产生资源，使研究人员能够进行功能基因组研究后，确定保护和推定的基因在DS-AD。