Thrombocytopoiesis in Diabetes: Role of Damage Associated Molecular Patterns

糖尿病中的血小板生成：损伤相关分子模式的作用

• 批准号: 9903444
• 负责人: Prabhakara Reddy Nagareddy
• 金额: $ 59.99万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-23 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9903444
• 关键词: Address; Adipose tissue; Affect; Antiplatelet Drugs; Applications Grants; Aspirin; Atherosclerosis; Binding; Biogenesis; Biological Assay; Blood; Blood Glucose; Blood Platelets; Bone Marrow; Cardiovascular Diseases; Chronic; Clinical; Complex; Complications of Diabetes Mellitus; Data; Diabetes Mellitus; Exhibits; Feedback; Genetic; Glucose; Glycosylated hemoglobin A; Hepatic; Hepatocyte; Hormones; Human; Hyperactivity; Hyperglycemia; IL6 gene; Immature Platelet; Impairment; Inflammation; Insulin-Dependent Diabetes Mellitus; Interleukin-6; Kidney; Kupffer Cells; Leukocytes; Ligands; Liver; Mediator of activation protein; Metabolic; Molecular; Mus; Myeloid Cells; Myelopoiesis; Non-Insulin-Dependent Diabetes Mellitus; Pathway interactions; Patients; Pattern; Pharmacology; Plasma; Platelet aggregation; Play; Production; Property; Reporting; Research; Resistance; Resolution; Risk; Role; S100A8 gene; Serum; Signal Pathway; Signal Transduction; Source; Stromal Cells; Testing; Thrombopoiesis; Thrombopoietin; base; diabetic patient; genetic approach; high risk; improved; in vivo; insulin sensitivity; liver inflammation; neutrophil; novel; novel therapeutics; platelet function; receptor; response; stem cells; thrombogenesis; tool; transcriptome; transcriptome sequencing; treatment strategy

Platelets play an important role in the initiation and propagation of atherosclerosis and, more so, in the ensuing atherothrombotic complications. Although the standard antiplatelet drugs reduce the risk of atherothrombotic complications in high-risk patients, they are not very effective in diabetes mellitus (DM) subjects. The reasons for this remains unclear but likely due to increased production/release of reticulated platelets (RP) from the bone marrow (BM). The RPs are immature, larger in size, hyperreactive, and less responsive to standard anti- platelet drugs. Platelet production is tightly regulated by the hormone thrombopoietin (TPO) and its receptor, c- MPL, which is found on several BM progenitor cells. While TPO is constitutively produced from BM stromal cells and the kidney, the liver becomes their major source during inflammation where hepatic TPO production is increased through the actions of interleukin-6 (IL-6). Our preliminary data suggests that hyperglycemia enhances platelet biogenesis via mechanisms that involve neutrophil-derived S100A8/A9, a Damage Associated Molecular Pattern (DAMP) complex, Kupffer cell (KC)-derived interleukin-6 (IL-6), and hepatic TPO. Studies in humans have also found a positive correlation between plasma S100A8/A9, IL-6, and platelet aggregation. Most importantly increased serum S100A8/A9 is associated with reduced anti-platelet effects of aspirin. Based on our preliminary data and the clinical evidence, we hypothesize that hyperglycemia-induced IL-6 production from hepatic KCs elevates plasma TPO and initiate thrombocytopoiesis resulting in higher proportion of RPs in the blood. The newly formed RPs, being hyperreactive, enhance platelet-leukocyte interactions and contribute to atherothrombotic complications. In order to test this hypothesis, firstly, we will examine how glucose enhances the production of RPs in diabetes. We will specifically identify the cross talk between circulating neutrophils and KCs by manipulating blood glucose, neutrophils, serum S100A8/A9 and RAGE/IL6 signaling in KCs and study how these manipulations affect RP production. Secondly, we will assess the atherogenic and thrombogenic properties of RPs in diabetes by performing various platelet function assays both in mice and type 2 DM subjects. The findings from these studies will have a broader impact on the current anti-platelet therapy particularly in DM subjects as there is a great potential for discovery of novel targets to treat cardiovascular disease.

血小板在动脉粥样硬化的启动和传播中起着重要的作用 动脉粥样硬化并发症。尽管标准抗血小板药物降低了动脉粥样硬化的风险 高危患者的并发症在糖尿病（DM）受试者中不是很有效。原因 为此尚不清楚，但可能是由于从 骨髓（BM）。 RP不成熟，大小较大，反应性过高，对标准抗的反应较少 血小板药物。血小板的产生受激素血栓蛋白（TPO）及其受体C-严格调节 MPL，在几个BM祖细胞上发现。而TPO是由BM Stromal组成的 细胞和肾脏，肝脏在肝TPO产生的炎症中成为主要来源 通过白介素6（IL-6）的作用增加。我们的初步数据表明高血糖 通过涉及中性粒细胞衍生的S100A8/A9的机制增强血小板生物发生 相关的分子模式（潮湿）复合物，库普弗细胞（KC）衍生的白介素-6（IL-6）和肝TPO。 人类的研究还发现血浆S100A8/A9，IL-6和血小板之间存在正相关。 聚合。最重要的是，血清S100A8/A9的增加与降低的抗血小板影响有关 阿司匹林。根据我们的初步数据和临床证据，我们假设高血糖诱导 肝KCS产生的IL-6产生升高血浆TPO并启动血小板tpoiesis，导致较高 RPS在血液中的比例。新形成的RP，具有过度反应性，增强了血小板 - 白细胞 相互作用并有助于动脉粥样硬化并发症。为了检验这一假设，首先，我们将 检查葡萄糖如何增强糖尿病中RP的产生。我们将特别识别串扰 通过操纵血糖，中性粒细胞，血清S100A8/A9和 KC中的RAGE/IL6信号传导，研究这些操作如何影响RP的产生。其次，我们将评估 通过执行各种血小板功能测定 在小鼠和2型D​​M受试者中。这些研究的发现将对当前产生更大的影响 抗血小板治疗，特别是在DM受试者中，因为发现新目标的潜力很大 治疗心血管疾病。