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.

Hutchinson-Gilford早衰综合征（HGPS）是第一个被确定的过早衰老综合征， 核纤层蛋白A的突变，核纤层蛋白的组成部分。HGPS患者通常在20岁之前死亡， 表现出加速老化的表型。突变核纤层蛋白A蛋白，也称为早老蛋白，直接破坏细胞核， 核纤层，导致核纤层相关染色质结构的改变，包括衰老增加， 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 在许多早老综合征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 不稳定性与老化。然而，核纤层的改变导致基因组维持的原因是， 缺陷并没有得到很好的理解。我们最近的结果揭示了基因组不稳定性的一个以前未知的起源 在早衰细胞中。具体地说，我们观察到早老蛋白表达会导致细胞内增殖的内在增加。 获得性DNA损伤的易感性。 我们的长期目标是阐明基因组中DNA损伤易感性的决定因素 在疾病和衰老中的维持和功能障碍。这项研究的直接目标是 确定DNA损伤易感性如何在早衰细胞中失调及其在衰老表型中的作用。 基于已发表的和我们的初步数据，我们假设早老蛋白表达改变染色质 结构和/或染色体定位，使细胞更容易受到DNA损伤积累， 加速细胞衰老表型的发生。我们将用创新的DNA损伤来检验这一假设- 我们实验室最近开发的映射技术，比较表观基因组分析，多重 染色体定位和与DNA损伤和衰老相关的细胞分析。基于我们 根据已公布的数据和初步数据，我们有能力完成以下具体目标：目标1： 确定调节早衰细胞中紫外线敏感性的表观遗传结构;目标2： 减少紫外线敏感性和细胞老化表型的表观遗传干预。的预期成果 这些研究包括：早老症细胞基因组中紫外线敏感性的高分辨率图谱; 确定染色质介导的调节过早老化细胞易感性的机制;以及 鉴定影响基因组稳定性和衰老表型的表观遗传靶点。这些理由 研究表明，一旦损伤易感性的机制在过早衰老的细胞中得到表征， 可以被操纵以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先前未被认识的起源，即 增加对损害的敏感性。这些调查的研究重点也是创新的，因为它 将揭示核纤层在防止遗传毒素暴露中的关键功能。这些研究将 这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。