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.

由于淀粉样蛋白的蛋白质和其他基因在染色体21上的基因的三次和过表达，因此患有唐氏综合征（DS）的个体在早期的AD神经病理比典型种群显示出AD的神经病理学，而大约一半的成年人DS发展AD。然而，DS的成年人存在广泛的表型变化，许多人没有发展AD。这项研究建议使用以前的生物群体样本来识别有助于DS成年人的AD弹性的因素。该项目将重新编程从有或没有伴随AD的较旧DS受试者中建立的成纤维细胞系，然后将其与诱导的多能干细胞（IPSC）（IPSC），然后将这些IPSC分化为神经元，然后将其分化为皮质器官（混合皮质神经元和星形胶质细胞3D培养）。这些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。 具体而言，该项目将使用一部分生物群体样品，这些样品检查了超过500名具有DS纵向的成年人来研究DS-AD。我们将：（1）重编程从具有或不使用DS-AD到IPSC的较旧DS受试者的成纤维细胞线，然后使用这些IPSC进行研究：（1）神经元发育对DS-AD的影响； （2）差异基因表达和eqtl； （3）新型基因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DS-AD中鉴定出保护性和推定基因后进行功能基因组研究。