Epigenetic Changes in Bone Marrow Progenitor Cells Impair Diabetic Wound Healing

描述(申请人提供)：尽管2型糖尿病(T2D)和周围血管疾病的治疗取得了重大进展，但伤口愈合率在过去30年中没有变化，每年有80,000例糖尿病患者因未愈合的伤口而截肢，相关的3年死亡率为20-50%。在糖尿病创面，慢性炎症状态是由免疫细胞(即巨噬细胞)产生的促炎和抗炎细胞因子之间的失衡所维持的。伤口中持续的促炎、M1巨噬细胞表型有效地阻止了愈合。由于这些外周免疫细胞大多来源于骨髓(BM)造血祖细胞，而且最近的证据表明表观遗传学在影响免疫细胞表型中起着关键作用，我们假设BM造血祖细胞的变化会导致外周表型的改变。为此，候选人(凯瑟琳·加拉格尔博士)试图研究骨髓水平的表观遗传学变化对外周巨噬细胞表型的作用以及随后对糖尿病伤口愈合的影响。该应用程序的总体目标是支持候选人作为一名基于免疫学的伤口愈合研究的独立研究员继续培训和发展。职业发展计划的基础是课程作业、导师的指导以及通过研究实际应用技能。候选人的主要研究目标是确定骨髓前体细胞是否发生了表观遗传变化，导致外周巨噬细胞表型“程序化和持久性”，这对T2D的伤口愈合产生了负面影响。候选人的主要研究兴趣反映在这项建议的具体目标中：(1)确定骨髓前体细胞的表观遗传学变化，并确定它们在糖尿病伤口愈合中对M1巨噬细胞表型的影响(2)确定脂肪组织营养/细胞因子导向的染色质修饰在T2D BM来源的祖细胞中的作用，以及(3)检测人T2D BM来源的造血干细胞(HSC)中组蛋白甲基化对M1表型的影响。这些研究的成功完成将增加我们对T2D BM来源的祖细胞的表观遗传学变化的病理作用以及它们对外周巨噬细胞和伤口愈合的影响的理解。

DESCRIPTION (provided by applicant): Despite significant advances in the treatment of Type 2 diabetes (T2D) and peripheral vascular disease, wound healing rates have not changed over the past 30 years, with 80,000 amputations performed annually for non-healing diabetic wounds with an associated 3-year mortality rate of 20-50%. In diabetic wounds, a chronic inflammatory state is maintained by imbalances between pro and anti-inflammatory cytokines produced by immune cells, namely macrophages. The persistent pro-inflammatory, M1 macrophage phenotype in the wound effectively prevents healing. Since these peripheral immune cells are mostly derived from bone marrow (BM) hematopoietic progenitor cells and recent evidence suggests that epigenetics plays a key role in influencing immune cell phenotypes, we hypothesize that changes in the BM progenitor cells result in altered peripheral phenotypes. To this end, the candidate (Dr. Katherine Gallagher) seeks to examine the role of epigenetic changes at the BM level on peripheral macrophage phenotypes and the subsequent influence on diabetic wound healing. The overall goal of this application is to support the candidate's continued training and development as an independent investigator in immunology-based, wound healing research. The career development plan is based on coursework, guidance from mentors, and the practical application of skills through research. The candidate's main research goals are to determine whether epigenetic changes occur in BM progenitor cells that result in a "programmed and persistent" peripheral macrophage phenotype, which negatively impacts wound healing in T2D. The major themes of the candidate's research interests are reflected in the Specific Aims of this proposal: (1) to identify epigenetic changes in BM progenitor cells and determine their influence on M1 macrophage phenotypes in diabetic wound healing (2) to determine the role of adipose tissue nutrient/cytokine-directed chromatin modifications in T2D BM-derived progenitor cells, and (3) to examine the influence of histone methylation in human T2D BM-derived hematopoietic stem cells (HSC) on the M1 phenotype. Successful completion of these studies should increase our understanding of the pathologic role of epigenetic changes on T2D BM-derived progenitor cells and their effect on peripheral macrophages and wound healing.