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

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

展开

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.

概括心血管梗死（MI）或中风，血小板驱动的事件。虽然预防继发性CVD的抗血小板疗法已良好，但通常不开处方抗血小板治疗，以防止首次MI或中风作为心脏保护益处被主要出血风险所抵消。血小板在MI和中风的发病机理中的完善作用以及缺乏针对原发性CVD预防的血小板指导的治疗选择需要研究新颖血小板靶标会影响血小板的多面作用而不会影响止血。此外，虽然血小板曾经被认为主要是止血和血栓形成的介质，但现在是了解它们是免疫介质的重要作用。血小板在慢性中扮演着核心角色从最初的先天免疫反应到损伤相关的分子，炎症会促进动脉粥样硬化模式蛋白与自适应免疫的参与。为了有效地瞄准该轴，可以更好地理解血小板促进动脉粥样硬化并抑制的途径和细胞通信网络需要CVD中的炎症分辨率。通过无偏的血小板测序，我们确定了一种新型的血小板激活反应的调节剂CD37。该建议旨在了解CD37如何调节血小板功能反应以及靶向血小板 CD37可能是减少（病原）生理血小板反应的可行治疗方法。在AIM 1中，我们将确定CD37在血小板激活反应中的作用并确定蛋白质结合伴侣在富含CD37的膜微区中。 AIM 2将评估靶向血小板CD37是否改变动脉粥样硬化和斑块稳定性。这些研究将是证明靶向的生存能力的基础血小板CD37减少血栓形成，动脉粥样硬化和全身性炎症。如果我们的假设证明了准确的CD37是我们新鉴定的血小板活性基因，可以针对预防和治疗多种血小板介导的疾病，包括心血管疾病。