The 4D nucleome of muscle regeneration in ischemia-induced tissue damage and repair

缺血引起的组织损伤和修复中肌肉再生的 4D 核组

• 批准号: 10487588
• 负责人: Yarui Diao
• 金额: $ 59.43万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-20 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10487588
• 关键词: 3-Dimensional; ATAC-seq; Affect; Age; Architecture; Automobile Driving; Bioinformatics; Biological Assay; Blood flow; Cardiovascular Diseases; Chromatin; Chromatin Loop; Chromatin Structure; Data; Data Set; Defect; Development; Diagnosis; Disease Progression; Enhancers; Etiology; Failure; Foundations; Future; Gene Expression; Gene Expression Regulation; Genetic Transcription; Genome; Hi-C; Human; In Vitro; Individual; Ischemia; Isolated limb perfusion; Lead; Limb Salvage; Limb structure; Muscle; Muscle satellite cell; Natural regeneration; Patients; Peripheral arterial disease; Persons; Phenotype; Play; Process; Regulator Genes; Research; Role; Skeletal Muscle; Structure; Testing; Tissues; United States; Work; critical limb Ischemia; human morbidity; human mortality; improved; innovation; limb amputation; muscle regeneration; novel; prevent; programs; promoter; regenerative; regenerative therapy; regenerative tissue; regenerative treatment; repaired; satellite cell; sex; stem cell self renewal; transcriptome sequencing; treatment strategy

ABSTRACT: Ischemia, caused by restriction of blood flow, often results in severe tissue damage. Critical limb ischemia (CLI) is a serious condition in which peripheral artery disease (PAD) leads to irreversible limb muscle damage. About 40% of CLI patients undergo limb amputation one year after diagnosis, and 50% die after five years. Current treatment options focus on improving limb perfusion but these often fail to prevent disease progression, pointing to a critical need for a deeper understanding of the basic mechanisms regulating human muscle regeneration and how they are disrupted by ischemic damage. In the long-term, this information may lead to new regenerative treatment strategies for limb salvage that are independent of limb perfusion. Recent studies suggest that failure of skeletal muscle regeneration is key to determining tissue loss in CLI versus repair. Successful muscle regeneration requires the orchestrated activation, proliferation and differentiation of muscle stem cells (MuSCs, also known as satellite cells) that are normally quiescent. In our preliminary analysis of MuSCs from one representative CLI patient, we found that the transcription of genes important for MuSC regeneration are dysregulated in ischemia, and that these changes are associated with rearrangements in 3D chromatin organization. These finding support the hypothesis that CLI involves a failure in the normal dynamic reorganization of 3D chromatin structure that orchestrates the regeneration of MuSCs. The overall objectives of this study are to identify the spatial-temporal changes of chromatin organization (the 4D nucleome, 4DN) normally associated with regenerative human MuSCs, and to understand the functional consequences of defects in this mechanism for muscle damage in CLI.

抽象的： 由血流限制引起的缺血通常会导致严重的组织损伤。严重肢体缺血 (CLI) 是一种严重的疾病，周围动脉疾病 (PAD) 会导致不可逆的肢体肌肉损伤。关于 40% 的 CLI 患者在诊断一年后接受截肢，50% 在五年后死亡。当前的 治疗方案的重点是改善肢体灌注，但这些往往无法阻止疾病进展， 指出迫切需要更深入地了解调节人体肌肉的基本机制 再生以及它们如何被缺血性损伤破坏。从长远来看，这些信息可能会导致 独立于肢体灌注的新的保肢再生治疗策略。最近的研究 表明骨骼肌再生失败是决定 CLI 中组织损失与修复的关键。 成功的肌肉再生需要精心策划的肌肉激活、增殖和分化 通常处于静止状态的干细胞（MuSC，也称为卫星细胞）。在我们初步分析中 来自一名代表性 CLI 患者的 MuSC，我们发现对 MuSC 重要的基因转录 缺血时再生失调，这些变化与 3D 重排有关 染色质组织。这些发现支持 CLI 涉及正常动态故障的假设 3D 染色质结构的重组协调 MuSC 的再生。总体目标 本研究的目的是确定染色质组织的时空变化（4D 核组，4DN） 通常与再生人类 MuSC 相关，并了解其功能后果 CLI 中肌肉损伤的这种机制的缺陷。