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

• 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
• 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

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 最终导致严重受损的主动脉壁破裂，危及生命。AAA的发生率是 不可接受的高。尽管在初级预防措施方面取得了进展，但AAA仍导致> 13000例死亡 美国每年因AAA破裂而死亡。因为在这些机制中存在着重大的知识差距， 导致持续的ECM降解持续存在，目前没有基于药物的治疗来规避AAA， 外科手术是克服或延缓病人负担的唯一选择。我们小组以前的工作 确定了神经元引导因子netrin-1在促进血管炎症中的工具作用。 受损血管壁中的跨壁巨噬细胞浸润是AAA的一个关键标志。农村妇女在消除 AAA中持续的ECM降解仍然知之甚少。本提案的目的是， netrin-1在维持AAA中ECM破坏中的作用。核心假设是巨噬细胞来源的 netrin-1是一种能够促进血管平滑肌细胞（VSMC）中MMP活化的病理信号， 这种串扰机制的破坏防止AAA中的病理性血管重塑。我们 理由是基于K99/R 00裁决期间的重要观察，即在K99/R 00裁决中没有netrin-1， 造血细胞（Ntn 1-/-）保护免于AAA发展和弹性蛋白断裂。单细胞RNA 测序显示netrin-1存在于透壁巨噬细胞中。重要的是， WT和Ntn 1-/-RT-PCR鉴定出在netrin-1缺陷小鼠的VSMC中MMP 3下调。在我们 具体目的，将使用巨噬细胞中netrin-1的组织特异性或条件性缺失的新小鼠模型， VSMC中MMP 3和再生蛋白（netrin-1的受体）的缺失，以确定这种指导信号如何 协调了一系列事件，通过促进催化酶的供应， 腹部组织这项研究具有创新性，因为我们研究了netrin-1在 介导串扰启动和有害的血管重塑，这是一种迄今为止尚未研究的机制， AAA。在结论中，我们将理解netrin-1在同步ECM损伤中的作用， AAA机制。这一贡献是显著的，因为我们将测试在AAA后靶向netrin-1是否是有效的。 建立的（诱导性缺失鼠模型）可以逆转ECM的降解并防止破裂。在 这种转化的方法，我们的数据将铺平道路，为发展有前途的预防性治疗 旨在靶向netrin-1或拮抗其信号传导事件以预防AAA的策略。