Macrophage and Vascular Smooth Muscle Cell dialogue: role in aortic aneurysm

巨噬细胞和血管平滑肌细胞对话：在主动脉瘤中的作用

基本信息

批准号：
10371182
负责人：
Bhama Ramkhelawon
金额：
$ 71.81万
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：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10371182
关键词：
Abdomen Abdominal Aortic Aneurysm Address Aneurysm Aorta Aortic Aneurysm Arteries Award Binding Blood Vessels CRISPR/Cas technology Cells Cessation of life Chronic Clinical Coculture Techniques Collagen Collagen Type IV Complex Coupled Cues Data Development Disease Dissection Elastin Engineering Enzymes Event Extracellular Matrix Extracellular Matrix Degradation Fostering Future Gene Deletion Hematopoietic Impairment Incidence Infiltration Inflammation Inflammatory Investigation Knowledge Lead Life Ligands MMP3 gene Matrix Metalloproteinases Medial Mediating Molecular Mus NTN1 gene Operative Surgical Procedures Pathogenesis Pathologic Pathway interactions Patients Pharmaceutical Preparations Pharmacology Positioning Attribute Preventive Preventive measure Process Reporting Research Role Rupture Ruptured Abdominal Aortic Aneurysm Series Signal Transduction Smooth Muscle Myocytes Stromal Cells Testing Therapeutic Therapeutic Intervention Tissue Model Tissues United States Up-Regulation Vascular Diseases Vascular Smooth Muscle Vascular remodeling Work abdominal aorta abdominal wall base experimental study healing high risk in vivo evaluation innovation insight loss of function macrophage mouse model neogenin netrin receptor neuronal guidance novel prevent programs receptor single-cell RNA sequencing transcriptome sequencing translational approach vascular inflammation

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 of the excessively damaged aortic wall. The incidence of AAA is unacceptably high. Despite progress in primary preventive measures, AAA still accounts for > 13000 deaths annually due to ruptured AAA in the United States. Because major knowledge gaps in the mechanisms that contribute to sustained ECM degradation persist, there is currently no drug-based therapy to circumvent AAA, surgery is the only alternative to overcome or delay the burden of patients. Previous work from our group has identified an instrumental role for the neuronal guidance cue, netrin-1 in fostering vascular inflammation. Transmural macrophage infiltration in the damaged vascular wall is a key hallmark of AAA. Their role in sustaining ECM degradation in AAA remains poorly understood. The objective of this proposal is to characterize the role of netrin-1 in sustaining ECM destruction in AAA. The central hypothesis is that macrophage-derived netrin-1 is a pathological signal capable of fueling MMP activation in vascular smooth muscle cells (VSMC) and the disruption of this cross-talk mechanism protects against pathological vascular remodeling in AAA. Our rationale is based on important observations made during K99/R00 award that the absence of netrin-1 in hematopoietic cells (Ntn1-/-) protects against AAA development and elastin fragmentation. Single cell RNA sequencing revealed that netrin-1 was harbored in transmural macrophages. Importantly, RNA sequencing of WT and Ntn1-/- aortas identified that MMP3 was downregulated in the VSMC in netrin-1-deficient mice. In our specific aims, will use novel mouse models of tissue-specific or conditional deletion of netrin-1 in macrophages, deletion of MMP3 and neogenin (the receptor of netrin-1) in VSMC to determine how this guidance cue orchestrates a series of events that lead to sustained ECM degradation by fueling the supply of catalytic enzymes to the abdominal tissue. The proposed research is innovative because we investigate the role netrin-1 in mediating cross-talk startegies and deleterious vascular remodeling, a heretofore-unexamined mechanism in AAA. Upon conclusion, we will understand the role of netrin-1 in synchronizing ECM damage via complex mechanisms in AAA. This contribution is significant since we will test whether targeting netrin-1 after AAA is established (inducible deletion murine models) can reverse the degradation of the ECM and prevent rupture. In this translational approach, our data will pave the way for the development of promising preventive therapeutic strategies aimed at targeting netrin-1 or antagonizing its signaling events to prevent AAA.

项目摘要腹主动脉瘤（AAA）是与炎症和上调有关的常见血管疾病基质 - 绝素蛋白酶（MMP）的局部降解，这些酶会导致细胞外基质（ECM）的局部降解过多损害的主动脉壁的威胁生命破裂。 AAA的发生率是高度高。尽管主要预防措施取得了进展，但AAA仍为13000人死亡每年由于美国的AAA破裂。因为在机制中的主要知识差距有助于持续的ECM降解持续存在，目前尚无基于药物的疗法来规避AAA，手术是克服或延迟患者负担的唯一替代方法。我们小组的先前工作有确定了神经元引导提示，Netrin-1在促进血管炎症中的作用。损坏的血管壁中的透视巨噬细胞浸润是AAA的关键标志。他们的作用维持AAA中的ECM降解仍然知之甚少。该提议的目的是表征 Netrin-1在维持AAA中ECM破坏中的作用。中心假设是巨噬细胞衍生 Netrin-1是一种病理信号，能够加油血管平滑肌细胞（VSMC）和这种串扰机制的破坏可以防止AAA中的病理血管重塑。我们的基本原理是基于在K99/R00奖励期间进行的重要观察结果，即缺乏Netrin-1 造血细胞（NTN1 - / - ）可预防AAA发育和弹性蛋白片段化。单细胞RNA 测序表明，Netrin-1是在透壁巨噬细胞中藏有的。重要的是，RNA测序的 WT和NTN1 - / - 主动脉确定MMP3在Netrin-1缺陷小鼠的VSMC中被下调。在我们的具体目的，将使用巨噬细胞中Netrin-1的组织特异性或条件缺失的新型小鼠模型， MMP3和Neogin（Netrin-1的受体）在VSMC中的缺失，以确定该指导如何提示策划了一系列事件，这些事件通过加油催化酶的供应来导致ECM降解到腹组织。拟议的研究具有创新性，因为我们研究了Netrin-1在介导串扰的起点和有害的血管重塑，这是一种迄今无验证的机制 AAA。总结一下，我们将了解Netrin-1通过复合物同步ECM损伤的作用 AAA的机制。这项贡献很重要，因为我们将测试AAA之后的Netrin-1是否为已建立的（可诱导的缺失鼠模型）可以扭转ECM的降解并防止破裂。在这种翻译方法，我们的数据将为开发有前途的预防治疗铺平道路旨在针对Netrin-1或对抗其信号事件以防止AAA的策略。