Impact of hematopoietic stem progenitor cell dysfunction on tissue recovery from ischemic injury in metabolic syndrome

越来越多的证据表明，与肥胖相关的健康问题，如胰岛素抵抗， 心血管疾病和受损的组织修复，伴有慢性炎症。虽然 已知失调的造血干细胞(HSPC)反应是 参与，肥胖导致炎症调节失调的机制(S) 而其对缺血后愈合的下游影响尚不清楚。长期的 这项研究的目的是了解肥胖和胰岛素 耐药性损害缺血损伤后的愈合，特别关注表观遗传学 HSPC的调节和炎症的调节失调。我们假设肥胖和 胰岛素抵抗导致HSPC失调，导致胰岛素供应增加 炎性单核细胞，进而导致长期炎症和 缺血组织损伤后愈合受阻。我们的初步数据表明，这 线粒体(MIT)-活性氧(ROS)诱导的表观遗传学途径 高脂饮食(HFD)诱导的糖尿病前期小鼠的失调。在这项研究中，我们建议： (1)研究糖尿病前期ROS在组蛋白-3赖氨酸-4(H3K4)中的作用 HSPC中的甲基化。我们假设HFD诱导的MIT-ROS增加H3K4me3 在HSPC中诱导Set7/9甲基转移酶和抑制JARID脱甲基酶 激活。(2)探讨糖尿病前期ROS在HSPC单核细胞生成中的作用 后肢缺血后。我们假设HFD增加了炎症性 MIT-ROS诱导H3K4me3诱导HSPC单系生成。(3)确定单元格 糖尿病前期异常的HSPC在组织修复中的自主作用 后肢缺血。我们假设糖尿病前期失调的HSPC增强 细胞自主性后肢缺血后的炎症和损害组织恢复 和MIT-ROS依赖的方式。我们建议的研究将开始阐明 肥胖相关疾病中HSPC失调的机制及其影响 关于缺血损伤后的炎症反应和愈合。如果成功，我们的数据 将MIT-ROS和下游H3K4甲基化作为诱导 糖尿病前期在HSPC中诱导的表观遗传记忆，并将为新的 糖尿病前期患者缺血性心血管疾病的治疗靶点 病理学。

Increasing evidence links obesity-related health problems, such as insulin resistance, cardiovascular disease and impaired tissue repair, with chronic inflammation. Although dysregulated hematopoietic stem progenitor cell (HSPC) responses are known to be involved, the mechanism(s) underlying obesity-induced dysregulation of inflammation and its downstream impact on healing following ischemia remain unclear. The long-term goal of this study is to understand mechanisms though which obesity and insulin resistance impairs healing after ischemic injury, with a specific focus on epigenetic regulation of HSPCs and dysregulation of inflammation. We hypothesize that obesity and insulin resistance induces HSPC dysregulation that leads to increased supply of inflammatory monocytes, which in turn contributes to prolonged inflammation and impaired healing after ischemic tissue injury. Our preliminary data suggest that this pathway involves mitochondria (mit)-reactive oxygen species (ROS)-induced epigenetic dysregulation in high fat diet (HFD)-induced prediabetic mice. In this study, we propose: (1) To determine the role of prediabetes-induced ROS in histone-3 lysine-4 (H3K4) methylation in HSPCs. We hypothesize that HFD-induced mit-ROS increases H3K4me3 in HSPCs by inducing SET7/9 methyltransferase and inhibiting JARID demethylase activation. (2) To determine the role of prediabetes-induced ROS in HSPC monopoiesis following hindlimb ischemia. We hypothesize that HFD increases inflammatory monopoiesis of HSPCs via mit-ROS-induced H3K4me3. (3) To determine the cell autonomous role of prediabetes-dysregulated HSPCs in tissue recovery following hindlimb ischemia. We hypothesize that prediabetes-dysregulated HSPCs enhance inflammation and impair tissue recovery after hindlimb ischemia in a cell-autonomous and mit-ROS-dependent manner. Our proposed study will begin to elucidate the mechanisms involved in HSPC dysregulation in obesity-related conditions and its impact on inflammatory responses and healing following ischemic injury. If successful, our data will implicate mit-ROS and downstream H3K4 methylation as a key pathway for inducing prediabetes-induced epigenetic memory in HSPCs, and will provide insight into novel therapeutic targets for ischemic cardiovascular diseases in patients with prediabetic pathology.