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（T2 D）和外周血管疾病的治疗方面取得了显著进展，但伤口愈合率在过去30年中没有变化，每年有80，000例截肢手术用于治疗不愈合的糖尿病伤口，相关的3年死亡率为20- 50%。在糖尿病伤口中，慢性炎症状态通过由免疫细胞（即巨噬细胞）产生的促炎细胞因子和抗炎细胞因子之间的不平衡来维持。伤口中持续的促炎性M1巨噬细胞表型有效地阻止愈合。由于这些外周免疫细胞主要来源于骨髓（BM）造血祖细胞和最近的证据表明，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，在BM祖细胞的变化导致改变外周表型。为此，候选人（凯瑟琳加拉格尔博士）试图研究外周巨噬细胞表型BM水平的表观遗传变化的作用，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基于免疫学的伤口愈合研究的独立调查员的持续培训和发展。职业发展计划是基于课程，导师的指导，并通过研究技能的实际应用。候选人的主要研究目标是确定BM祖细胞中是否发生表观遗传变化，导致“程序化和持久性”外周巨噬细胞表型，这对T2 D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）鉴定BM祖细胞中的表观遗传变化并确定它们对糖尿病伤口愈合中的M1巨噬细胞表型的影响（2）确定脂肪组织营养素/精氨酸定向的染色质修饰在T2 D BM衍生的祖细胞中的作用，以及（3）检测人T2 D BM衍生的造血干细胞（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表观遗传变化对T2 D BM衍生祖细胞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.