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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

基本信息

批准号：
10661563
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
项目类别：
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/10661563
关键词：
Abdominal Aortic Aneurysm Acceleration 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 Creativeness Data Death Rate Development Disease Elastin Engineering Event Exposure to Extracellular Matrix Extracellular Matrix Degradation Family member Fostering Genetic Glycoproteins Growth Factor Homing Image Incidence Inflammation Inflammatory Investigation Knockout Mice Knowledge Leucine Leukocytes Life Lung Lung Transplantation MPL gene Macrophage Macrophage Activation 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 Platelet Activation Platelet Inhibitors Platelet aggregation Prevalence Preventive Production Proteins Proteome Reporter Research Role Rupture Series Signal Transduction Testing Therapeutic Therapeutic Intervention Thrombopoietin Tissues Trachea Transfusion Transplantation Up-Regulation Vascular Diseases Vascular remodeling Work experimental study high risk human RNA sequencing immune function immunoregulation innovation insight leucine-rich repeat protein loss of function migration monocyte mouse model novel prevent receptor recruit single-cell RNA sequencing stem transcriptome vascular inflammation vascular injury vector

项目摘要

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.

项目总结

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Mechanical Reprogramming of Macrophages: A Push for Vascularization.

巨噬细胞的机械重编程：推动血管化。

DOI：
10.1161/atvbaha.123.319030
发表时间：
2023
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
0
作者：
Ramkhelawon,Bhama
通讯作者：
Ramkhelawon,Bhama

Linking single nucleotide polymorphisms to signaling blueprints in abdominal aortic aneurysms.

DOI：
10.1038/s41598-022-25144-y
发表时间：
2022-12-05
期刊：
SCIENTIFIC REPORTS
影响因子：
4.6
作者：
Lim, Chrysania;Pratama, Muhammad Yogi;Rivera, Cristobal;Silvestro, Michele;Tsao, Philip S. S.;Maegdefessel, Lars;Gallagher, Katherine A. A.;Maldonado, Thomas;Ramkhelawon, Bhama
通讯作者：
Ramkhelawon, Bhama