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: 10117691
• 负责人: Yarui Diao
• 金额: $ 60.95万
• 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/10117691
• 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; Human; In Vitro; Individual; Ischemia; Isolated limb perfusion; Lead; Limb Salvage; Limb structure; Muscle; Muscle satellite cell; Natural regeneration; Patients; Peripheral arterial disease; Phenotype; Play; Process; Regulator Genes; Research; Role; Skeletal Muscle; Structure; Testing; Tissues; United States; Work; cell regeneration; critical limb Ischemia; human morbidity; human mortality; improved; innovation; limb amputation; muscle regeneration; novel; prevent; programs; promoter; regenerative; regenerative therapy; repaired; satellite cell; sex; 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： 缺血是由于血流限制引起的，通常会导致严重的组织损害。临界肢体缺血（CLI） 是一种严重的疾病，其中外周动脉疾病（PAD）会导致不可逆的肢体损伤。关于 40％的CLI患者在诊断后一年接受肢体截肢，五年后死亡50％。当前的 治疗方案的重点是改善肢体灌注，但通常无法防止疾病进展， 指出对调节人类肌肉的基本机制有更深入的理解的迫切需要 再生以及它们如何被缺血损害破坏。从长远来看，这些信息可能会导致 独立于肢体灌注的肢体打捞的新再生治疗策略。最近的研究 表明骨骼肌再生的失败是确定CLI与修复中组织损失的关键。 成功的肌肉再生需要精心策划的激活，增殖和肌肉的分化 干细胞（MUSC，也称为卫星细胞）通常是静止的。在我们对 来自一名代表性CLI患者的MUSC，我们发现基因的转录对MUSC很重要 缺血中的再生失调，这些变化与3D的重排有关 染色质组织。这些发现支持CLI涉及正常动态失败的假设 策划MUSC再生的3D染色质结构的重组。总体目标 这项研究是为了确定染色质组织的时空变化（4D核心，4DN） 通常与再生性人类MUSC相关，并了解 CLI中肌肉损伤机制缺陷。