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：
10132381
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/10132381
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.

项目概要腹主动脉瘤 (AAA) 是一种与炎症和上调相关的常见血管疾病基质金属蛋白酶 (MMP)，导致细胞外基质 (ECM) 局部降解最终导致过度受损的主动脉壁破裂，危及生命。 AAA 的发病率是高得令人无法接受。尽管初级预防措施取得了进展，AAA 仍然导致超过 13000 人死亡在美国，每年都会因 AAA 破裂而发生。因为机制方面存在重大知识差距导致持续的 ECM 降解持续存在，目前没有基于药物的疗法来规避 AAA，手术是克服或延缓患者负担的唯一选择。我们小组之前的工作有确定了神经元引导信号 netrin-1 在促进血管炎症中的重要作用。受损血管壁中的透壁巨噬细胞浸润是 AAA 的一个重要标志。他们的角色 AAA 中 ECM 持续降解的机制仍知之甚少。该提案的目的是描述 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的 netrin-1 是一种病理信号，能够促进血管平滑肌细胞 (VSMC) 中的 MMP 激活，这种串扰机制的破坏可以防止 AAA 中的病理性血管重塑。我们的基本原理基于 K99/R00 授予期间进行的重要观察，即 Netrin-1 的缺失造血细胞 (Ntn1-/-) 可防止 AAA 发育和弹性蛋白断裂。单细胞RNA 测序结果显示，netrin-1 存在于跨壁巨噬细胞中。重要的是，RNA 测序 WT 和 Ntn1-/- 主动脉发现 netrin-1 缺陷小鼠的 VSMC 中 MMP3 下调。在我们的具体目标，将使用巨噬细胞中组织特异性或条件性删除 netrin-1 的新型小鼠模型，删除 VSMC 中的 MMP3 和 neogenin（netrin-1 的受体）以确定该指导信号如何发挥作用协调一系列事件，通过促进催化酶的供应导致 ECM 持续降解到腹部组织。拟议的研究具有创新性，因为我们研究了 netrin-1 在介导串扰策略和有害的血管重塑，这是迄今为止未经检验的机制 AAA。得出结论后，我们将了解 netrin-1 在通过复杂的同步 ECM 损伤中的作用 AAA 中的机制。这一贡献很重要，因为我们将测试 AAA 后是否靶向 netrin-1 建立的（诱导缺失小鼠模型）可以逆转 ECM 的降解并防止破裂。在这种转化方法，我们的数据将为开发有前景的预防性治疗铺平道路旨在针对 netrin-1 或拮抗其信号事件以预防 AAA 的策略。