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 progeria综合征（HGP）是首次确定的早熟综合征 层粘连蛋白A的突变，核层的一个成分。 HGPS患者通常在20岁之前死亡， 表现出加速的衰老表型。突变层层蛋白A蛋白（也称为孕激素）直接破坏核 薄片，导致层状相关染色质结构的改变，包括衰老和 对DNA破坏剂的敏感性。特别是，DNA损伤反应缺陷和基因组增加 在许多后代综合征和正常老年细胞中都观察到了不稳定性，从而连接了基因组 衰老的不稳定性。但是，核椎板改变导致基因组维持的原因 缺陷尚不清楚。我们最近的结果揭示了先前未知的基因组不稳定性的起源 在后代细胞中。具体而言，我们观察到过程表达会导致内在增加 获得DNA病变的敏感性。 我们的长期目标是描述基因组中DNA损伤敏感性的决定因素 维护及其在疾病和衰老方面的功能障碍。该提案中研究的直接目标是 确定如何在后代细胞中解除DNA损伤易感性及其在衰老表型中的作用。 根据已发布的和我们的初步数据，我们假设过程表达会改变染色质 结构和/或染色体定位，使细胞更容易受到DNA病变的积累和 加速细胞衰老表型的发作。我们将使用创新的DNA病变 - 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 染色体图和与DNA损伤和衰老相关的细胞测定。基于我们 已发布和初步数据，我们的位置是完成以下特定目的：AIM 1： 确定调节后代细胞中紫外线敏感性的表观遗传体系结构；目标2：确定 降低紫外线敏感性和细胞衰老表型的表观遗传干预措施。预期的结果 这些研究包括：跨后代细胞基因组的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的机制；和 鉴定影响基因组稳定性和衰老表型的表观遗传靶标。这些理由 研究是，一旦在过早的衰老细胞中表征了损伤易感性的机制 可以操纵以消除由基因组不稳定性引发的衰老表型。这项研究很重要 因为它揭示了先前无法识别的HGPS细胞基因组不稳定性的来源 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 将揭示核椎板在预防基因毒素暴露中的关键功能。这些研究会 可能会扩大我们对典型衰老的理解，并揭示干预的可能机制。