Origin and Immune Functions of Platelets in Aortic Aneurysms

主动脉瘤中血小板的起源和免疫功能

• 批准号: 10239240
• 负责人: Bhama Ramkhelawon
• 金额: $ 59.48万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10239240
• 关键词: Abdominal Aortic Aneurysm; Agonist; Alpha Granule; Aorta; Aortic Aneurysm; Aortic Rupture; Autocrine Communication; Behavior; Biogenesis; Blood; Blood Platelets; Blood Vessels; Bone Marrow; Bone Marrow Transplantation; CRISPR/Cas technology; Cells; Clinical; Complex; Coupled; Data; Death Rate; Development; Disease; Elastin; Engineering; Event; Exposure to; Extracellular Matrix; Extracellular Matrix Degradation; Family member; Fostering; Genetic; Growth Factor; Homing; Image; Incidence; Inflammation; Inflammatory; Investigation; Knockout Mice; Knowledge; Leucine; Leukocytes; Life; Lung; Lung Transplantation; MPL gene; Maps; Matrix Metalloproteinases; Mediating; Megakaryocytes; Molecular; Molecular Profiling; Mus; Operative Surgical Procedures; Organ; Paracrine Communication; Pathologic; Pathway interactions; Patients; Peripheral arterial disease; Pharmaceutical Preparations; Phenotype; Plant Roots; Platelet Activation; Platelet Inhibitors; Prevalence; Preventive; Production; Proteins; Proteome; Reporter; Research; Role; Rupture; Series; Signal Transduction; Testing; Therapeutic; Therapeutic Intervention; Thrombopoietin; Tissues; Transfusion; Transplantation; Up-Regulation; Vascular Diseases; Vascular remodeling; Work; base; experimental study; high risk; human RNA sequencing; immune function; immunoregulation; innovation; insight; leucine-rich repeat protein; loss of function; macrophage; migration; monocyte; mouse model; novel; prevent; receptor; recruit; single-cell RNA sequencing; stem; transcriptome; vascular inflammation; vascular injury; vector

Project Summary Abdominal aortic aneurysm (AAA) is a common vascular disorder associated with inflammation and upregulation of matrix-metalloproteinases (MMP), which cause the local degradation of the extracellular matrix (ECM) culminating in life-threatening rupture. The incidence of AAA is unacceptably high and still accounts for high death rates. There are major knowledge gaps in the mechanisms that contribute to ECM degradation hindering the pipelines of drug-based therapy. Surgery is the only alternative to overcome the burden of patients. The presence of transmural macrophage (MØ) in the damaged vascular wall is a key hallmark of AAA. Their role in sustaining ECM degradation remains poorly understood. Previous work from our group has identified instrumental molecular signals that foster MØ activation in AAA. New preliminary data show that MØ can also be activated by cellular platelet entities, through their non-canonical inflammatory potential. Activated platelets originating from the lungs but not the bone marrow (BM) illustrated enhanced capacities of mediating such effects. The objective of this proposal is to investigate the contribution of immuno-active platelets in regulating MØ-dependent ECM destruction in AAA. The central hypothesis is that lung-derived platelets are pathological players capable of assisting monocyte recruitment and subsequent activation of MØ proteolytic phenotype thereby promoting AAA. Our rationale is based on important observations that the depletion of platelets, dampened transmural MØ content, elastin fragmentation and reduced AAA. Transfusion of lung platelets but not those originating from the BM accelerated the rate of aortic dilation and induced aortic rupture. Single-cell RNA sequencing of AAA and platelet-depleted tissues provided a vista of immunoregulatory networks synchronized by circulating platelets in the vasculature amongst which leucine-rich repeat protein family member was one of the most downregulated in the aorta exposed to platelet depletion and was distinctly enriched in lung platelets and in monocyte-platelets clusters in the blood. Treatment of mice with an inhibitor of platelet activation, reduced monocyte recruitment, MØ activation and AAA. In our specific aims, will use novel genetic thrombocytopenic mice models combined with BM transplantation of platelet-specific conditional reporter mice as well as conditional deletion of identified target to investigate the contribution of lung and BM platelets in promoting pathological inflammation in AAA. Mechanistic studies will reveal series of pathways and events orchestrated by lung platelets that culminate in injury of the vascular wall. The proposed research is provocative and innovative because we investigate the role of lung platelets in mediating deleterious vascular remodeling, a heretofore- unexamined mechanism in AAA. This contribution is significant since we will test whether specific targeting of leucine-rich protein in platelets from the lungs can protect against AAA and will pave the way for the development of promising preventive therapeutic strategies to curb AAA.

项目摘要 腹主动脉瘤（AAA）是一种常见的与炎症和上调相关的血管疾病 基质金属蛋白酶（MMP），其引起细胞外基质（ECM）的局部降解 最终导致危及生命的破裂AAA的发生率高得令人无法接受， 死亡率在导致ECM降解的机制方面存在重大知识缺口， 药物治疗的管道。手术是克服患者负担的唯一选择。的 在受损的血管壁中存在透壁巨噬细胞（MMCs）是AAA的关键标志。农村妇女在消除 持续ECM降解仍然知之甚少。我们小组以前的工作已经确定了 工具分子信号，促进AAA中的MMP 3激活。新的初步数据显示， 由细胞血小板实体通过其非典型的炎症潜能激活。活化的血小板 来源于肺而不是骨髓（BM）说明了增强的介导这种免疫应答的能力。 方面的影响.这项建议的目的是研究免疫活性血小板在调节免疫功能中的作用。 腹主动脉瘤中依赖于细胞外基质的破坏。中心假设是肺源性血小板是病理性的 能够辅助单核细胞募集和随后激活MMP 3蛋白水解表型的参与者 从而促进AAA。我们的理论基础是重要的观察结果，即血小板的减少， 抑制透壁肌松质含量、弹性蛋白断裂和减少AAA。输注肺血小板，但 来自BM的那些加速了主动脉扩张的速率并诱发主动脉破裂。单细胞RNA AAA和血小板耗竭组织的测序提供了同步的免疫调节网络的前景， 通过在脉管系统中循环血小板，其中富含亮氨酸的重复蛋白家族成员是 在暴露于血小板耗竭的主动脉中下调最多，在肺血小板中明显富集 以及血液中的单核细胞-血小板簇。用血小板活化抑制剂治疗小鼠，减少 单核细胞募集、MRF活化和AAA。在我们的具体目标，将使用新的遗传多态性 小鼠模型结合骨髓移植的血小板特异性条件报告小鼠以及 条件性删除已鉴定的靶点，以研究肺和BM血小板在促进血小板活化中的作用。 AAA中的病理性炎症。机制研究将揭示一系列的途径和事件精心策划的 最终导致血管壁损伤的肺血小板。拟议的研究是挑衅性和创新性的 由于我们研究了肺血小板在介导有害血管重塑中的作用，因此迄今为止， AAA中未检查的机制。这一贡献是重要的，因为我们将测试是否有具体的目标， 来自肺部的血小板中富含亮氨酸的蛋白质可以防止AAA，并为AAA的发展铺平道路。 有希望的预防性治疗策略来遏制AAA。