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Base excision repair, premature senescence and aging in Down syndrome

唐氏综合症的碱基切除修复、早衰和衰老

基本信息

批准号：
8699653
负责人：
DIANE C CABELOF
金额：
$ 19万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-15 至 2016-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Down syndrome (DS) is a condition of intellectual disability characterized by accelerated aging. The broad, long-term objective of this project is to identify the cause(s) of aging in Down syndrome, with a particular emphasis on investigating the role of DNA repair in the aging phenotype observed in Down syndrome. The hypothesis is that the aging phenotype of Down syndrome results from lifelong inhibition of BER induced by chromosome 21-linked miRNA overexpression. This hypothesis will be tested in the following Specific Aims: Specific aim 1: Determine whether miR-155 and/or miR-802 stable overexpression alone or in combination recapitulate the BER and senescence phenotypes of Down syndrome (DS). Pol¿ promoter activity, BER capacity, and senescence will be evaluated. The ability of MeCP2 and/or Creb1 expression to restore BER will also be evaluated. In parallel the impact of pol¿ nullizygosity on senescence induction will be determined. This will allow a directly connection between BER loss and senescence to be established. Specific aim 2: Determine whether silencing of either miR-155 or miR-802 in primary DS fibroblasts reverses the DS-induced inhibition of BER and whether that then prevents early senescence. These data would directly tie chromosome 21-mediated miRNA overexpression to BER capacity and senescence. Further, to test whether miRNA overexpression inhibits BER through MeCP2-mediated signaling, MeCP2 and CREB1 will be overexpressed in DS lines to determine both whether this ameliorates the BER phenotype of DS and whether either may be an appropriate interventional target. Specific aim 3: Down syndrome provides a unique opportunity to investigate the role of senescence as a barrier to tumorigenesis in a relevant, in vivo model. The Ts65DN mouse model of DS is known to recapitulate much of the DS phenotype, including accelerated aging (to the extent it has been evaluated) and premature senescence in ex vivo fibroblasts. Thorough pathological and morphological analysis of tissues over time will be evaluated in this model. In addition we will determine miR-155 and miR-802 expression, pol¿/BER capacity and senescence in a panel of tissues to begin to identify which tissues exhibit aging phenotypes in the DS model. These experiments will generate critical information to justify further aging studies and interventional strategies in this mouse model.

描述（由申请人提供）：唐氏综合症（DS）是一种以加速衰老为特征的智力障碍疾病。该项目的广泛、长期目标是确定唐氏综合症衰老的原因，特别强调研究 DNA 修复在唐氏综合症中观察到的衰老表型中的作用。该假设认为，唐氏综合症的衰老表型是由 21 号染色体连锁 miRNA 过度表达引起的 BER 终生抑制所致。该假设将在以下具体目标中进行检验：具体目标 1：确定 miR-155 和/或 miR-802 单独或组合稳定过表达是否能概括唐氏综合症 (DS) 的 BER 和衰老表型。将评估 Pol¿ 启动子活性、BER 容量和衰老。还将评估 MeCP2 和/或 Creb1 表达恢复 BER 的能力。同时将确定多合性无效对衰老诱导的影响。这将允许在 BER 损失和老化之间建立直接联系。具体目标 2：确定原代 DS 成纤维细胞中 miR-155 或 miR-802 的沉默是否可以逆转 DS 诱导的 BER 抑制，以及是否可以防止早期衰老。这些数据将直接将 21 号染色体介导的 miRNA 过度表达与 BER 容量和衰老联系起来。此外，为了测试 miRNA 过表达是否通过 MeCP2 介导的信号传导抑制 BER，MeCP2 和 CREB1 将在 DS 系中过表达，以确定这是否改善 DS 的 BER 表型以及是否可以作为适当的干预靶点。具体目标 3：唐氏综合症提供了一个独特的机会，可以在相关的体内模型中研究衰老作为肿瘤发生屏障的作用。众所周知，DS 的 Ts65DN 小鼠模型能够重现 DS 的大部分表型，包括加速衰老（在已评估的范围内）和离体成纤维细胞的过早衰老。该模型将评估随时间推移对组织进行彻底的病理学和形态学分析。此外，我们将确定一组组织中的 miR-155 和 miR-802 表达、pol¿/BER 能力和衰老，以开始识别哪些组织在 DS 模型中表现出衰老表型。这些实验将产生关键信息，以证明该小鼠模型中进一步的衰老研究和干预策略的合理性。