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: 10377308
• 负责人: Prabhakara Reddy Nagareddy
• 金额: $ 54.09万
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10377308
• 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，更重要的是，在随后的 动脉粥样硬化血栓并发症。尽管标准的抗血小板药物可降低动脉粥样硬化血栓形成的风险 对于高危患者的并发症，它们对糖尿病(DM)患者并不是很有效。原因何在 这一点尚不清楚，但可能是由于网织血小板(RP)的产生/释放增加所致 骨髓(BM)。RPS不成熟，体积较大，反应过度，对标准的抗病毒反应较差 血小板药物。血小板的生成受到激素促血小板生成素(TPO)及其受体c-TPO的严格调控。 MPL，存在于多个BM祖细胞上。而TPO是由BM基质构成的 细胞和肾脏，肝脏在炎症期间成为它们的主要来源，肝脏产生TPO 通过白介素6(IL-6)的作用而增加。我们的初步数据显示，高血糖 通过涉及中性粒细胞来源的S100A8/A9损伤的机制促进血小板的生物生成 相关分子模式(DAMP)复合体、库普弗细胞(KC)来源的白介素6(IL-6)和肝脏TPO。 对人类的研究也发现，血浆S100A8/A9、IL-6与血小板呈正相关 聚合。最重要的是，血清S100A8/A9的升高与抗血小板作用的降低有关 阿司匹林。根据我们的初步数据和临床证据，我们假设高血糖导致 肝KCs产生IL-6升高血浆TPO，启动血小板生成，导致 血液中RPS的比例。新形成的RPS具有高反应性，能增强血小板-白细胞 相互作用，并导致动脉粥样硬化血栓并发症。为了验证这个假设，首先，我们将 研究葡萄糖如何促进糖尿病患者RPS的产生。我们将具体确定相声 通过调节血糖、中性粒细胞、血清S100A8/A9和 RAGE/IL6在KCs中的信号转导，并研究这些操作如何影响RP的产生。其次，我们将评估 不同血小板功能测定对糖尿病患者RPS致动脉粥样硬化和血栓形成特性的影响 在小鼠和2型糖尿病受试者中都有。这些研究的发现将对当前的 抗血小板治疗，特别是在糖尿病患者中，因为发现新的靶点具有巨大的潜力 治疗心血管疾病。