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: 10683263
• 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/10683263
• 关键词: 3-Dimensional; ATAC-seq; Affect; Age; Architecture; Automobile Driving; Bioinformatics; Biological Assay; Blood flow; Cardiovascular Diseases; Cell Separation; 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; Limb Salvage; Limb structure; Muscle; Muscle satellite cell; Natural regeneration; Patients; Peripheral arterial disease; Persons; Phenotype; Play; Process; Proliferating; 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.

摘要： 血流受限引起的缺血通常会导致严重的组织损伤。严重肢体缺血(CLI) 是一种严重的外周动脉疾病(PAD)导致不可逆的四肢肌肉损伤。关于 40%的CLI患者在确诊后一年接受截肢手术，50%的患者在五年后死亡。当前 治疗方案的重点是改善肢体血流，但这些往往无法阻止疾病的进展， 指出迫切需要更深入地了解调节人类肌肉的基本机制 再生，以及它们是如何被缺血损伤破坏的。从长远来看，这些信息可能会导致 新的不依赖肢体灌流的保肢再生治疗策略。最新研究 提示骨骼肌再生失败是决定CLI与修复中组织丢失的关键。 成功的肌肉再生需要肌肉的激活、增殖和分化。 通常处于静止状态的干细胞(MuSCs，也称为卫星细胞)。在我们初步分析中 从一名有代表性的CLI患者的MUSCs中，我们发现MUSC基因的转录对MUSC很重要 再生在缺血时是失调的，这些变化与3D中的重排有关 染色质组织。这些发现支持CLI与正常动态中的故障有关的假设 重组3D染色质结构，协调MSC的再生。总体目标 这项研究的目的是确定染色质组织(4D核体，4dN)的时空变化 通常与再生性人类MUSCs相关，并了解 CLI中肌肉损伤的这种机制存在缺陷。