Epigenetic Changes in Bone Marrow Progenitor Cells Impair Diabetic Wound Healing

描述（由申请人提供）：尽管在2型糖尿病（T2D）和周围血管疾病的治疗方面取得了重大进展，但伤口愈合率在过去30年中没有改变，每年有80,000例未愈合的糖尿病伤口截肢，相关的3年死亡率为20-50%。在糖尿病伤口中，免疫细胞（即巨噬细胞）产生的促炎性和抗炎性细胞因子之间的不平衡维持了慢性炎症状态。伤口中持续的促炎，M1巨噬细胞表型有效地阻止愈合。由于这些外周免疫细胞大多来自骨髓造血祖细胞，最近的证据表明，表观遗传学在影响免疫细胞表型方面起着关键作用，我们假设骨髓祖细胞的改变会导致外周表型的改变。为此，候选人（Dr. Katherine Gallagher）试图研究BM水平的表观遗传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。本申请的总体目标是支持候选人在基于免疫学的伤口愈合研究中作为独立研究者的持续培训和发展。职业发展计划以课程作业、导师指导和通过研究实际应用技能为基础。该候选人的主要研究目标是确定BM祖细胞是否发生表观遗传变化，从而导致“程序性和持久性”外周巨噬细胞表型，这对T2D的伤口愈合产生负面影响。候选人研究兴趣的主要主题反映在本提案的具体目标中：(1)确定糖尿病伤口愈合中BM祖细胞的表观遗传变化并确定其对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源性祖细胞中的作用；(3)研究人T2D BM源性造血干细胞（HSC）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脑梗死源性祖细胞的表观遗传变化的病理作用及其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.