Origins of Genome Instability in Progeria

早衰症基因组不稳定的起源

• 批准号: 9979662
• 负责人: Ashby J. Morrison
• 金额: $ 19.71万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-15 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9979662
• 关键词: Age; Aging; Alopecia; Architecture; Base Pairing; Biological Assay; Bone Density; Cell Aging; Cells; Cellular Assay; ChIP-seq; Chromatin; DNA Adducts; DNA Damage; DNA Methylation; DNA lesion; Data; Defect; Deoxyribonucleases; Disease; Epigenetic Process; Excision; Exhibits; Exposure to; Fatty acid glycerol esters; Fluorescent in Situ Hybridization; Functional disorder; Future; Genome; Genome Stability; Genomic Instability; Goals; Heterochromatin; Intervention; Investigation; Kinetics; Lamin Type A; Link; Maintenance; Maps; Measures; Mediating; Monitor; Mutagens; Mutation; Nuclear; Nuclear Lamina; Outcome Study; Patients; Phenotype; Positioning Attribute; Predisposition; Premature aging syndrome; Progeria; Proteins; Public Health; Publishing; Pyrimidine Dimers; Radial; Research; Resolution; Role; Syndrome; Techniques; Testing; Therapeutic Intervention; UV Radiation Exposure; UV induced; Ultraviolet Rays; base; cell age; cell determination; cell type; chromosomal location; comparative; epigenomics; fitness; genome-wide; histone methylation; histone modification; inhibitor/antagonist; innovation; mutant; novel; prevent; repaired; response; senescence; subcutaneous; ultraviolet damage; ultraviolet lesions

Hutchinson-Gilford Progeria Syndrome (HGPS) was the first identified premature aging syndrome caused by mutation of lamin A, a component of the nuclear lamina. HGPS patients typically die before the age of 20 and exhibit accelerated aging phenotypes. Mutant lamin A protein, also called progerin, directly disrupts the nuclear lamina, resulting in alteration of lamina-associated chromatin architecture, including increased senescence and sensitivity to DNA damaging agents. In particular, DNA damage response defects and increased genome instabilities have been observed in many progeroid syndromes and normal aged cells, thereby linking genome instability with aging. However, the reasons why alteration of the nuclear lamina causes genome maintenance defects is not well understood. Our recent results reveal a previously unknown origin of genome instability in progeria cells. Specifically, we observe that progerin expression results in an intrinsic increase in susceptibility to acquire DNA lesions. Our long-term goal is to delineate the determinants of DNA damage susceptibility in genome maintenance and its dysfunction in disease and aging. The immediate goal of the research in this proposal is to determine how DNA damage susceptibility is deregulated in progeria cells and its role in aging phenotypes. Based on published and our preliminary data, we hypothesize that progerin expression alters chromatin architecture and/or chromosomal positioning, rendering cells more susceptible to DNA lesion accumulation and accelerating onset of cellular aging phenotypes. We will test this hypothesis using innovative DNA lesion- mapping techniques that our lab has recently developed, comparative epigenomic analysis, multi-plex chromosomal mapping, and cellular assays associated with DNA damage and senescence. Based on our published and preliminary data, we are ideally positioned to complete the following Specific Aims: Aim 1: Determine the epigenetic architectures that regulate UV susceptibility in progeria cells; and Aim 2: Identify epigenetic interventions that reduce UV susceptibility and cellular aging phenotypes. Expected outcomes from these studies include: high resolution maps of UV susceptibility across the genome of progeria cells; the determination of the chromatin-mediated mechanisms that regulate susceptibility in prematurely aging cells; and identification of epigenetic targets that influence genome stability and aging phenotypes. The rationale for these studies is that once the mechanisms of damage susceptibility are characterized in premature aging cells they can be manipulated to abrogate aging phenotypes initiated by genome instabilities. This research is significant because it reveals a previously unrecognized origin of genome instabilities in HGPS cells, namely increased susceptibility to damage. The research focus of these investigations is also innovative because it will reveal the critical function of the nuclear lamina in protecting against genotoxin exposure. These studies will likely to expand our understanding of typical aging and reveal possible mechanisms for intervention.

哈钦森-吉尔福德早衰综合症 (HGPS) 是第一个被确定的早衰综合症，由以下因素引起： 核纤层蛋白 A 的突变，核纤层的一个组成部分。 HGPS 患者通常在 20 岁之前死亡 表现出加速衰老的表型。突变核纤层蛋白 A 蛋白，也称为早老蛋白，直接破坏细胞核 层，导致层相关染色质结构的改变，包括衰老和衰老的增加 对 DNA 损伤剂的敏感性。特别是 DNA 损伤反应缺陷和基因组增加 在许多早衰综合症和正常衰老细胞中观察到不稳定性，从而将基因组联系起来 随老化而不稳定。然而，核纤层的改变导致基因组维持的原因 缺陷还没有被很好地理解。我们最近的结果揭示了之前未知的基因组不稳定的起源 在早衰细胞中。具体来说，我们观察到早老蛋白表达导致内在增加 获得 DNA 损伤的易感性。 我们的长期目标是描绘基因组中 DNA 损伤易感性的决定因素 维护及其在疾病和衰老中的功能障碍。本提案中研究的直接目标是 确定早衰细胞中 DNA 损伤敏感性如何失调及其在衰老表型中的作用。 根据已发表的数据和我们的初步数据，我们假设早老蛋白的表达会改变染色质 结构和/或染色体定位，使细胞更容易受到 DNA 损伤积累的影响， 加速细胞衰老表型的发生。我们将使用创新的 DNA 损伤来测试这个假设 - 我们实验室最近开发的绘图技术、比较表观基因组分析、多重分析 染色体作图以及与 DNA 损伤和衰老相关的细胞测定。基于我们的 根据已发布的初步数据，我们完全有能力完成以下具体目标：目标 1： 确定调节早衰细胞紫外线敏感性的表观遗传结构；目标 2：识别 表观遗传干预可降低紫外线敏感性和细胞衰老表型。预期成果 这些研究包括：早衰细胞基因组紫外线敏感性的高分辨率图；这 确定调节过早衰老细胞易感性的染色质介导机制；和 识别影响基因组稳定性和衰老表型的表观遗传目标。这些的理由 研究表明，一旦早衰细胞的损伤易感性机制得到表征，它们就会 可以通过操纵来消除由基因组不稳定性引发的衰老表型。这项研究意义重大 因为它揭示了 HGPS 细胞中基因组不稳定性的一个以前未被认识的起源，即 增加对损坏的敏感性。这些调查的研究重点也具有创新性，因为 将揭示核纤层在防止基因毒素暴露方面的关键功能。这些研究将 可能会扩大我们对典型衰老的理解并揭示可能的干预机制。