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

造血干祖细胞功能障碍对代谢综合征缺血性损伤组织恢复的影响

• 批准号: 9987107
• 负责人: Norifumi Urao
• 金额: $ 40.5万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9987107
• 关键词: Address; Adoptive Transfer; Adult; Blood; Bone Marrow; Bone Marrow Stem Cell; Bone Marrow Transplantation; Cardiovascular Diseases; Cell Transplantation; Cell Transplants; Cell physiology; Cells; Chronic; Cytometry; Data; Epigenetic Process; Event; Exhibits; Functional disorder; Genes; Genetic; Genome; Goals; Health; Health Care Costs; Hematopoietic stem cells; High Fat Diet; Hindlimb; Histones; Impaired wound healing; Impairment; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Injury; Insulin Resistance; Ischemia; Lead; Limb structure; Link; Lysine; Magnetic Resonance Imaging; Metabolic syndrome; Methylation; Methyltransferase; Mitochondria; Monocytosis; Mus; Muscle; Obesity; Pathology; Pathway interactions; Patients; Pharmacology; Population; Pre-Clinical Model; Prediabetes syndrome; Reactive Oxygen Species; Recovery; Risk; Role; Spleen; Testing; Thinness; Tissues; Vascular Diseases; bioluminescence imaging; epigenetic memory; epigenetic regulation; experimental study; genetic manipulation; healing; histone modification; improved; in vivo; inhibitor/antagonist; insight; monocyte; new therapeutic target; novel; novel therapeutics; obesity development; public health relevance; response

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.

越来越多的证据表明与肥胖相关的健康问题存在关联，例如胰岛素抵抗、 心血管疾病和组织修复受损，伴有慢性炎症。虽然 已知造血干祖细胞 (HSPC) 反应失调 涉及肥胖引起的炎症失调的机制 其对缺血后愈合的下游影响仍不清楚。长期来看 这项研究的目的是了解肥胖和胰岛素之间的机制 抵抗力会损害缺血性损伤后的愈合，特别关注表观遗传 HSPC 的调节和炎症失调。我们假设肥胖和 胰岛素抵抗会导致 HSPC 失调，从而导致胰岛素供应增加 炎症单核细胞，进而导致长期炎症和 缺血性组织损伤后愈合受损。我们的初步数据表明，这 途径涉及线粒体（mit）-活性氧（ROS）诱导的表观遗传 高脂肪饮食（HFD）诱导的糖尿病前期小鼠的失调。在本研究中，我们建议： (1) 确定糖尿病前期诱导的 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 通过诱导 SET7/9 甲基转移酶并抑制 JARID 去甲基酶在 HSPC 中发挥作用 激活。 (2) 确定糖尿病前期诱导的ROS在HSPC垄断中的作用 后肢缺血后。我们假设 HFD 会增加炎症 通过 mit-ROS 诱导的 H3K4me3 实现 HSPC 的垄断。 (3) 确定小区 糖尿病前期失调的 HSPC 在组织恢复中的自主作用 后肢缺血。我们假设糖尿病前期失调的 HSPC 会增强 细胞自主性后肢缺血后炎症并损害组织恢复 和mit-ROS依赖的方式。我们提出的研究将开始阐明 肥胖相关疾病中 HSPC 失调的机制及其影响 缺血性损伤后的炎症反应和愈合。如果成功的话，我们的数据 将暗示 mit-ROS 和下游 H3K4 甲基化是诱导的关键途径 HSPC 中糖尿病前期诱导的表观遗传记忆，并将提供新的见解 糖尿病前期患者缺血性心血管疾病的治疗靶点 病理。