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Mechanism of Nuclear Defects in Hutchinson-Gilford Progeria Syndrome

哈钦森-吉尔福德早衰综合症的核缺陷机制

基本信息

批准号：
7576814
负责人：
Yue Zou
金额：
$ 5.85万
依托单位：
EAST TENNESSEE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-03-01 至 2011-02-28
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Cellular accumulation of DNA double strand breaks (DSBs) has been widely suggested to be a hallmark step leading to premature aging, cellular senescence, and aging. However, how DSB can accumulate in the cells that have intact DSB repair genes remains unknown. Our recent unexpected novel findings on the possible involvement of xeroderma pigmentosum group A (XPA) in the laminopathy-based premature aging, typically Hutchinson-Gilford progeria syndrome (HGPS), open an opportunity to address this challenging question. Interestingly, the same lamin A-related molecular mechanism responsible for HGPS was recently found to be active in human aging. Although XPA, a protein exclusively involved in nucleotide excision repair (NER), has no role in DSB repair, our preliminary data showed that XPA dysfunctionally localizes to DSB sites in laminopathy-based premature aging cells, implying the possible blockage of the recruitment of DSB repair proteins to the damage sites for repair. Strikingly, siRNA knockdown of XPA in the progeroid cells partially restored DSB repair. The goal of this project is to delineate the molecular basis of DSB accumulation and the role of XPA in laminopathy-related premature aging, particularly HGPS, and aging, and to gain a potential major advance in understanding the basic mechanisms of premature aging and aging. We will test the main hypothesis that XPA plays an important role in development of accelerated aging. The investigation will be carried out in five Specific Aims: (1) To elucidate the molecular basis of XPA-DSB mislocalization in progeria cells; and (2) To determine the effects of XPA-DSB mislocalization on cellular DNA damage responses. Due to its novelty and potential impact, this project may involve considerable risk but represents a highly innovative effort with the potential to lead to a breakthrough in understanding the mechanism of premature aging and aging, which fits well into the theme of pilot or feasibility studies of the Small Grant Program. Public Health Relevance: Aging which is a normal, but puzzling biological process, not only governs human lifespan, but also significantly reduces the quality of life due to the development of gerontological diseases. On the other hand, abnormal aging such as premature aging is a typical phenotype of devastating progeria diseases. While it is believed that one of the major causes to premature aging and aging is the accumulation of DNA damage in cells, the underlying molecular mechanism remains elusive. This project represents an initial or pilot effort with a long-term goal aiming to delineate the mechanisms of human premature aging and aging, and to provide a molecular basis for future development of novel strategies for better treatment of progeria and gerontological diseases.

描述（由申请人提供）：DNA 双链断裂（DSB）的细胞积累已被广泛认为是导致过早衰老、细胞衰老和衰老的标志性步骤。然而，DSB 如何在具有完整 DSB 修复基因的细胞中积累仍然未知。我们最近关于 A 组色素性干皮病 (XPA) 可能参与基于纤维病的过早衰老（通常是哈钦森-吉尔福德早衰综合症 (HGPS)）的意外新发现为解决这一具有挑战性的问题提供了机会。有趣的是，最近发现负责 HGPS 的核纤层蛋白 A 相关分子机制在人类衰老过程中也很活跃。尽管XPA（一种专门参与核苷酸切除修复（NER）的蛋白质）在DSB修复中没有作用，但我们的初步数据表明，在基于核纤层病的过早衰老细胞中，XPA功能失调地定位于DSB位点，这意味着可能会阻碍DSB修复蛋白募集到损伤位点进行修复。引人注目的是，早衰细胞中 XPA 的 siRNA 敲低部分恢复了 DSB 修复。该项目的目标是描绘 DSB 积累的分子基础以及 XPA 在核纤层病相关的过早衰老（特别是 HGPS）和衰老中的作用，并在理解过早衰老和衰老的基本机制方面取得潜在的重大进展。我们将检验 XPA 在加速衰老的发展中发挥重要作用的主要假设。该研究将围绕五个具体目标进行：（1）阐明早衰细胞中XPA-DSB错误定位的分子基础； (2) 确定 XPA-DSB 错误定位对细胞 DNA 损伤反应的影响。由于其新颖性和潜在影响，该项目可能涉及相当大的风险，但代表了一项高度创新的努力，有可能在理解早衰和衰老机制方面带来突破，这非常适合小额赠款计划试点或可行性研究的主题。公共卫生相关性：衰老是一种正常但令人费解的生物过程，不仅影响人类的寿命，而且由于老年疾病的发展而显着降低生活质量。另一方面，异常衰老如早衰是毁灭性早衰性疾病的典型表型。虽然人们认为过早衰老和衰老的主要原因之一是细胞中 DNA 损伤的积累，但其潜在的分子机制仍然难以捉摸。该项目代表了初步或试点工作，其长期目标旨在描述人类过早衰老和衰老的机制，并为未来开发更好地治疗早衰和老年疾病的新策略提供分子基础。