Cerebral Aneurysm Healing: Cellular Mediators, Mechanisms, and Downstream Actions

脑动脉瘤愈合：细胞介质、机制和下游作用

• 批准号: 8691246
• 负责人: Brian Lim Hoh
• 金额: $ 32.72万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8691246
• 关键词: Address; Aneurysm; Angiography; Applications Grants; Autopsy; Biological Assay; Bone Marrow; CCL2 gene; Cardiac; Cells; Cerebral Aneurysm; Characteristics; Clip; Collagen; Connective Tissue; Cutaneous; Data; Dependency; Development; Endothelial Cells; Fibroblasts; Fibrosis; Future; Goals; Healed; Health; Human; Hyperplasia; Immunohistochemistry; Implant; In Vitro; Inflammatory; Intercellular adhesion molecule 1; Interleukin-6; Knowledge; Mediating; Mediator of activation protein; Methods; Mission; Modeling; Monocyte Chemoattractant Protein-1; Morbidity - disease rate; Mus; Myocardial Infarction; Oryctolagus cuniculus; Outcome; Patients; Pharmaceutical Preparations; Platinum; Population; Process; Public Health; Publishing; Recurrence; Regulation; Research; Research Personnel; Retreatment; Role; Rupture; Signal Transduction; Site; Smooth Muscle Myocytes; Source; Specimen; Surgical Clips; T-Lymphocyte; Testing; Tissues; Transgenic Organisms; Tumor Necrosis Factor-alpha; Ventricular; Work; Wound Healing; angiogenesis; base; disability; healing; improved; innovation; macrophage; monocyte chemoattractant protein 1 receptor; mortality; mouse model; neutralizing antibody; neutrophil; novel

DESCRIPTION (provided by applicant): The current treatment for cerebral aneurysms (CA) is clipping or coiling. Coiling seems to be safer than clipping, but is associated with significant rates of aneurysm recurrence and need to retreat patients. Published findings demonstrate successfully healed aneurysms that do not recur are characterized by tissue ingrowth containing macrophages, connective tissue proliferation, fibroblasts, collagen, smooth muscle cells, and angiogenesis. Our studies demonstrate MCP-1-releasing coils implanted into murine aneurysms produce aneurysm tissue ingrowth that is 25% greater than seen with standard platinum coils. There is a fundamental gap in knowledge, though, about the mechanisms of aneurysm healing, and specifically, the role of MCP-1. The objective of this application is to address this gap in knowledge by defining the role, mechanisms, and downstream mediators of MCP-1 in aneurysm healing. Based on our preliminary results, the central hypothesis is that MCP-1 is necessary for aneurysm healing which is directed by cell-specific populations and regulated by downstream mediators to create tissue ingrowth in the aneurysm lumen. The central hypothesis will be tested with the three aims of this New Investigator-initiated grant application: Hypothesis I: MCP-1 is necessary for aneurysm healing and acts locally at the aneurysm site. Aim 1A. Demonstrate and cross-validate MCP-1 is necessary for aneurysm healing. Aim 1B. Demonstrate MCP-1 acts locally vs. systemically in aneurysm healing. Hypothesis II: MCP-1-mediated aneurysm healing is directed by circulating and resident cell-specific populations in a defined sequential manner. Aim 2A. Define the temporal sequence of cell-specific populations that direct MCP-1-mediated aneurysm healing. Aim 2B. Determine the source of cell-specific populations (circulating vs. resident) that direct MCP-1-mediated aneurysm healing. Hypothesis III: MCP-1-mediated aneurysm healing is regulated by downstream mediators. Aim 3A. Define the downstream mediators of MCP- 1-mediated aneurysm healing. Aim 3B. Demonstrate regulation of MCP-1-mediated aneurysm healing by downstream mediators. Aim 3C. Cross-validate downstream mediators in human aneurysm specimens. The proposed application is innovative because of: 1) our murine carotid aneurysm model; 2) a new method for performing angiography in our murine carotid aneurysm model; 3) our method for coating coils to sustain- release mediators for local delivery to aneurysms; 4) our focus on understanding the mechanisms of MCP-1; and 5) use of human aneurysm specimens. This work is significant because it is directly translatable and deliverable to patients. Future directions, once we have established the mechanisms in a mouse model, will be testing in a rabbit aneurysm model, which is the direct precursor to human trial.

描述(申请人提供)：目前治疗脑动脉瘤(CA)的方法是夹闭或弹簧圈。弹簧圈似乎比夹闭术更安全，但与动脉瘤复发率和患者需要撤退有关。已发表的研究结果表明，成功治愈且不复发的动脉瘤的特征是组织内长入含有巨噬细胞、结缔组织增殖、成纤维细胞、胶原、平滑肌细胞和血管生成。我们的研究表明，将单核细胞趋化蛋白-1释放的弹簧圈植入小鼠动脉瘤可产生比标准铂金弹簧圈多25%的动脉瘤组织生长。然而，关于动脉瘤愈合的机制，特别是MCP-1的作用，人们的认识存在着根本性的差距。这项应用的目的是通过定义MCP-1在动脉瘤愈合中的作用、机制和下游介质来解决这一知识差距。根据我们的初步结果，中心假设是MCP-1是动脉瘤愈合所必需的，它由细胞特异性群体指导，并受下游介质调节，在动脉瘤管腔内产生组织内生。中心假说将通过这项由新调查者发起的赠款申请的三个目标进行检验：假说I：MCP-1是动脉瘤愈合所必需的，并在动脉瘤部位发挥局部作用。目标1 A。证明和交叉验证MCP-1对于动脉瘤愈合是必要的。目标1B。证明单核细胞趋化蛋白-1在动脉瘤愈合中局部作用与全身作用。假设II：单核细胞趋化蛋白-1介导的动脉瘤愈合是由循环和常驻细胞特异性群体以确定的顺序方式指导的。目标2 A。确定指导MCP-1介导的动脉瘤愈合的细胞特异性群体的时间序列。目标2B。确定引导单核细胞趋化蛋白-1介导的动脉瘤愈合的细胞特异性群体(循环与常驻)的来源。假设III：单核细胞趋化蛋白-1介导的动脉瘤愈合受下游介质的调节。目标3A。明确单核细胞趋化蛋白-1介导的动脉瘤愈合的下游介质。目标3B。演示下游介质对MCP-1介导的动脉瘤愈合的调节作用。目标是3C。交叉验证人体动脉瘤标本中的下游介质。拟议的应用具有创新性，因为：1)我们的小鼠颈动脉瘤模型；2)在我们的小鼠颈动脉瘤模型中进行血管造影术的新方法；3)我们为局部输送的动脉瘤包裹弹簧圈以维持释放介质的方法；4)我们专注于了解MCP-1的机制；以及5)使用人类动脉瘤标本。这项工作意义重大，因为它是可直接翻译和交付给患者的。一旦我们在小鼠模型中建立了这些机制，未来的方向将是在兔动脉瘤模型上进行测试，这是人类试验的直接先驱。