CD37 as a Regulator of Platelet Patho(Physiological) Responses

CD37 作为血小板病理（生理）反应的调节剂

基本信息

批准号：
10638254
负责人：
Tessa Barrett
金额：
$ 59.17万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-15 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10638254
关键词：
Acceleration Affect Affinity Chromatography Agonist Area Arterial Fatty Streak Arteries Atherosclerosis Binding Binding Proteins Biological Response Modifiers Blood Platelets Bone Marrow Cardiovascular Diseases Cardiovascular system Cell Communication Cells Cellular Indexing of Transcriptomes and Epitopes by Sequencing Cessation of life Chronic Clinical Cytometry Data Development Disease Event Foundations Genes Hemorrhage Hemostatic Agents Hemostatic function Human IL6 gene Individual Inflammation Inflammatory Innate Immune Response Integrins Knockout Mice Knowledge Leukocytes Macrophage Mass Spectrum Analysis Mediating Mediator Membrane Microdomains Mesentery Microscopy Modeling Molecular Mus Myocardial Infarction Outcome Pathogenesis Pathway interactions Patients Pattern Phenocopy Phenotype Physiological Platelet Activation Platelet aggregation Play Primary Prevention Protein Binding Domain Proteins Resolution Rest Risk Role Signal Transduction Signaling Protein Stenosis Stroke Testing Therapeutic Thrombosis Thrombus Time Transplantation adaptive immunity affinity labeling arteriole atherogenesis atherothrombosis cardioprotection cardiovascular disorder prevention cohort follow-up in vivo indexing insight monocyte mouse model new therapeutic target novel novel therapeutics prevent receptor recruit response shear stress systemic inflammatory response transcriptome sequencing transcriptomics vascular injury

项目摘要

SUMMARY Eighty-five percent (85%) of cardiovascular disease deaths occur due to either myocardial infarction (MI) or stroke, platelet-driven events. While antiplatelet therapy for secondary CVD prevention is well-established, antiplatelet therapy is not commonly prescribed to prevent a first MI or stroke as the cardioprotective benefits are offset by major bleeding risk. The well-established role of platelets in the pathogenesis of MI and stroke and the lack of platelet-directed therapeutic options for primary CVD prevention necessitates investigating novel platelet targets which would impact the multifaceted effects of platelets without impacting hemostasis. Furthermore, while platelets were once considered primarily mediators of hemostasis and thrombosis, it is now understood that they play an important role as immune mediators. Platelets play central roles in the chronic inflammation that fuels atherosclerosis, from the initial innate immune response to damage-associated molecular pattern proteins to the engagement of adaptive immunity. To effectively target this axis, a better understanding of the pathways and cell-cell communication networks by which platelets promote atherogenesis and inhibit inflammation resolution in CVD Is required. By unbiased platelet sequencing, we have identified a novel regulator of platelet activation responses, CD37. This proposal aims to understand how CD37 regulates platelet functional responses and how targeting platelet CD37 may be a viable therapeutic approach to reduce (patho)physiological platelet responses. In Aim 1 we will establish the role of CD37 in platelet activation responses and identify protein-binding partners in CD37-enriched membrane microdomains. Aim 2 will assess if targeting platelet CD37 alters atherosclerosis and plaque stability. The studies will serve as an essential foundation to demonstrate the viability of targeting platelet CD37 to reduce thrombosis, atherogenesis, and systemic inflammation. If our hypotheses prove accurate, CD37, our newly identified platelet activity gene, could be targeted to prevent and treat a wide variety of platelet-mediated disorders, including cardiovascular disease.

概括百分之八十五 (85%) 的心血管疾病死亡是由于心肌梗死 (MI) 或中风、血小板驱动事件。虽然用于二级 CVD 预防的抗血小板治疗已十分成熟，抗血小板治疗通常不用于预防首次心肌梗死或中风，因为其具有心脏保护作用被大出血风险所抵消。血小板在 MI 和中风发病机制中的明确作用由于缺乏针对 CVD 一级预防的血小板导向治疗方案，因此有必要研究新的治疗方法血小板靶标将影响血小板的多方面作用而不影响止血。此外，虽然血小板曾经被认为是止血和血栓形成的主要介质，但现在它被认为是止血和血栓形成的主要介质。了解它们作为免疫介质发挥着重要作用。血小板在慢性疾病中发挥核心作用炎症促进动脉粥样硬化，从最初的先天免疫反应到损伤相关分子模式蛋白质参与适应性免疫。为了有效地瞄准这个轴，更好地理解血小板促进动脉粥样硬化形成和抑制的途径和细胞间通讯网络 CVD 中的炎症需要得到解决。通过无偏的血小板测序，我们发现了一种新型的血小板激活反应调节因子 CD37。该提案旨在了解CD37如何调节血小板功能反应以及如何靶向血小板 CD37 可能是减少（病理）生理血小板反应的可行治疗方法。在目标 1 中，我们将确定 CD37 在血小板激活反应中的作用并鉴定蛋白质结合伙伴富含 CD37 的膜微区。目标 2 将评估靶向血小板 CD37 是否会改变动脉粥样硬化和斑块稳定性。这些研究将作为证明靶向可行性的重要基础血小板 CD37 可减少血栓形成、动脉粥样硬化和全身炎症。如果我们的假设证明准确地说，我们新发现的血小板活性基因 CD37 可用于预防和治疗多种疾病血小板介导的疾病，包括心血管疾病。