Platelet Metabolism in Diabetes Mellitus

糖尿病中的血小板代谢

基本信息

批准号：
10705023
负责人：
Qingjun Wang
金额：
$ 53.15万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-20 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10705023
关键词：
Acute Address Affect Animal Model Arterial Injury Binding Biological Assay Biology Blood Glucose Blood Platelets Blood Vessels Blood coagulation Buffers Calcium Carbon Cardiovascular system Cause of Death Chelating Agents Citric Acid Cycle Clot retraction Coagulation Process Consumption Data Development Diabetes Mellitus Doctor of Philosophy Enzymes Event Fibrin Fructose Genetic Gluconeogenesis Glucose Glucose Transporter Glucosephosphate Dehydrogenase Glycogen Glycogen Phosphorylase Glycolysis Heart Diseases Hemostatic function Homeostasis Human Hyperactivity Hyperglycemia Impairment In Vitro Incidence Insulin-Dependent Diabetes Mellitus Kentucky Kinetics Knowledge Lead Learning Literature Mediating Metabolic Metabolic Pathway Metabolism Middle Cerebral Artery Occlusion Modeling Morbidity - disease rate Mus Myocardial Infarction NADP Obstruction Operative Surgical Procedures Outcome Oxidation-Reduction Pathogenicity Patients Pentose Phosphate Cycle Pathway Pentosephosphate Pathway Phosphoric Monoester Hydrolases Phosphorylases Platelet Activation Positioning Attribute Production Protein Dephosphorylation Pulmonary Embolism Reactive Oxygen Species Reduced Glutathione Regulation Reporting Rest Risk Risk Reduction Rodent Role Source Streptozocin Stroke Testing Thrombin Thrombosis Thrombus Traction Universities chelation diabetic patient first responder glucose metabolism glucose uptake glycemic control glycogen metabolism in vivo inhibitor metabolomics mortality mouse model new therapeutic target novel novel therapeutic intervention pharmacologic platelet function stable isotope stroke risk thrombotic tool

项目摘要

Project Summary/Abstract Heart disease and stroke are the No. 1 and 5 causes of deaths in the US. Type 1 diabetes mellitus (T1DM) significantly increases the risk for heart attacks and strokes. Intense glycemic control has been reported to reduce major cardiovascular events by >30%, suggesting that hyperglycemia is one of the major contributors to T1DM-associated heart attack and stroke risk escalation. However, how T1DM and hyperglycemia exacerbate such risk is unclear. Platelets are vascular first-responders that activate for hemostasis upon blood vessel damage; whereas pathogenic platelet activation leads to spurious thrombosis and acute vascular obstruction. T1DM and hyperglycemia lead to platelet hyperactivity and increased propensity to form thrombi. This proposals aims to understand how hyperglycemia causes platelet hyperactivity and thrombosis in T1DM, and to develop new therapeutic strategies to mitigate T1DM-associated heart attacks and strokes. Utilizing an integrated metabolism toolkit including state-of-the-art Stable Isotope Resolved Metabolomics (SIRM), we demonstrated critical role of altered platelet metabolism in thrombin-induced platelet activation. Specifically, thrombin stimulation alters platelet metabolism that is centered on glycogen metabolism, pentose phosphate pathway (PPP), and fructose 1,6-bisphosphate (F1,6BP), namely, “the glycogen-PPP-F1,6BP axis”, modulating energy, redox and calcium homeostasis in platelets and leading to their activation. Literature and our compelling preliminary data further reveal that hyperglycemia increases glycogen storage and its mobilization that generates ATP, PPP inhibition, reactive oxygen species, and intracellular calcium, all of which are in line with increased propensity for platelets to activate. Therefore, our overarching hypothesis is that hyperglycemia changes the glycogen-PPP-F1,6BP axis in platelets to drive platelet hyperactivity and thus thrombotic risk in T1DM. In Aim 1, we will delineate these hyperglycemia-induced changes in the glycogen-PPP-F1,6BP axis in platelets isolated from T1DM patients and normal healthy platelets subject to acute hyperglycemia in vitro. In Aim 2, we will determine how modulation of the glycogen-PPP-F1,6BP axis by pharmacological and genetic means suppresses hyperglycemia-induced platelet hyperactivity in vitro. In Aim 3, we will determine how modulation of the glycogen- PPP-F1,6BP axis by pharmacological and genetic means reduces hyperglycemia-exacerbated thrombosis and stroke in animal models. Our team is in a unique position to address our hypothesis, as we possess recognized expertise in metabolism and metabolomics (Qingjun Wang PhD and Matthew Gentry PhD), platelet biology (Sidney Whiteheart PhD), T1DM (Lisa Tannock MD), and stroke (Justin Fraser MD and Jill Roberts PhD), and we have strong partnership with the University of Kentucky Metabolomics, Redox Metabolism, and Rodent Surgery Cores. Upon completion of the proposed project, we will have presented a novel mechanism for metabolic dysregulation in platelets to mediate hyperglycemia-induced platelet hyperactivity and thrombosis in T1DM, and will have identified new therapeutic targets for mitigating T1DM-associated heart attacks and strokes.

项目概要/摘要心脏病和中风是美国 1 型糖尿病 (T1DM) 死亡的第一大和第五大原因。据报道，严格的血糖控制会显着增加心脏病和中风的风险。减少主要心血管事件超过 30%，表明高血糖是导致心血管事件发生的主要原因之一然而，T1 型糖尿病相关的心脏病发作和中风风险升级，以及高血糖如何恶化。这种风险尚不清楚。血小板是血管第一反应者，可在血管上激活止血。而致病性血小板活化会导致假性血栓形成和急性血管阻塞。 T1DM 和高血糖会导致血小板过度活跃并增加形成血栓的倾向。旨在了解高血糖如何导致 T1DM 患者血小板过度活跃和血栓形成，并开发减轻 T1DM 相关心脏病和中风的新治疗策略。我们展示了代谢工具包，包括最先进的稳定同位素解析代谢组学 (SIRM) 血小板代谢改变在凝血酶诱导的血小板活化中的关键作用。改变以糖原代谢、磷酸戊糖途径为中心的刺激血小板代谢（PPP）和果糖1,6-二磷酸（F1,6BP），即“糖原-PPP-F1,6BP轴”，调节能量，血小板中的氧化还原和钙稳态并导致其激活的文献和我们引人注目的。初步数据进一步表明，高血糖会增加糖原的储存及其动员，从而产生 ATP、PPP 抑制、活性氧和细胞内钙，所有这些都与增加有关因此，我们的首要假设是高血糖会改变血小板的激活倾向。血小板中的糖原-PPP-F1,6BP 轴可驱动血小板过度活跃，从而提高 T1DM 中的血栓形成风险。我们将描述分离的血小板中糖原-PPP-F1,6BP 轴的这些高血糖引起的变化在目标 2 中，我们将在体外研究来自 T1DM 患者和正常健康血小板的急性高血糖。确定如何通过药理学和遗传手段调节糖原-PPP-F1,6BP 轴抑制在目标 3 中，我们将确定如何调节糖原-体外高血糖诱导的血小板过度活跃。 PPP-F1,6BP轴通过药理学和遗传手段减少高血糖加剧的血栓形成和正如我们所认识到的那样，我们的团队处于解决我们的假设的独特地位。代谢和代谢组学方面的专业知识（王庆军博士和马修·金特里博士）、血小板生物学（Sidney Whiteheart 博士）、T1DM（Lisa Tannock 医学博士）和中风（Justin Fraser 医学博士和 Jill Roberts 博士），以及我们与肯塔基大学代谢组学、氧化还原代谢和啮齿动物建立了牢固的合作伙伴关系手术核心。完成拟议的项目后，我们将提出一种新的机制。血小板代谢失调介导高血糖诱导的血小板过度活跃和血栓形成 T1DM，并将确定减轻 T1DM 相关心脏病和中风的新治疗靶点。