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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

基本信息

批准号：
10220954
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
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10220954
关键词：
Address Adoptive Transfer Adult Blood Bone Marrow Bone Marrow Stem Cell Bone Marrow Transplantation Cardiovascular Diseases Cell Transplantation 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 healing Impaired wound healing Impairment In Vitro Inflammation Inflammatory Inflammatory Response Insulin Resistance Ischemia Lead 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 critical limb Ischemia epigenetic memory epigenetic regulation experimental study genetic manipulation healing histone modification improved in vivo inhibitor/antagonist insight ischemic injury limb ischemia monocyte new therapeutic target novel novel therapeutics obese patients obesity development public health relevance response stem cell function tissue injury

项目摘要

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，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，慢性炎症。虽然已知失调的造血干祖细胞（HSPC）应答是造血干/祖细胞（HSPC）的一个重要组成部分。肥胖引起的炎症失调的潜在机制其对局部缺血后愈合的下游影响仍不清楚。长期这项研究的目的是了解肥胖和胰岛素耐药性损害缺血性损伤后的愈合，特别关注表观遗传 HSPC的调节和炎症的失调。我们假设肥胖和胰岛素抵抗诱导HSPC失调，导致胰岛素供应增加，炎症单核细胞，这反过来又有助于长期炎症，缺血性组织损伤后愈合受损。我们的初步数据表明，途径涉及线粒体（mit）-活性氧（ROS）诱导的表观遗传在高脂饮食（HFD）诱导的前驱糖尿病小鼠中，在这项研究中，我们建议： (1)为了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SET 7/9甲基转移酶和抑制JARID脱甲基酶 activation. (2)确定糖尿病前期诱导的ROS在HSPC单细胞生成中的作用后肢缺血后。我们假设HFD增加了炎症反应，通过mit-ROS诱导的H3K4me3的HSPC的单细胞生成。(3)以确定电池糖尿病前期失调的HSPC在糖尿病后组织恢复中的自主作用后肢缺血我们假设糖尿病前期HSPCs失调增强了后肢缺血后炎症和受损组织恢复在细胞自主和mit-ROS依赖性方式。我们提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对缺血性损伤后炎症反应和愈合的影响。如果成功，我们的数据将暗示mit-ROS和下游H3K4甲基化是诱导细胞凋亡的关键途径。糖尿病前期诱导的HSPC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