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: 9242079
• 负责人: Brian Lim Hoh
• 金额: $ 32.81万
• 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/9242079
• 关键词: Address; Aneurysm; Angiography; Applications Grants; Autopsy; Biological Assay; Bone Marrow; CCL2 gene; Cardiac; Cells; Cerebral Aneurysm; Characteristics; Collagen; Connective Tissue; Cutaneous; Data; Dependency; Development; Endothelial Cells; Fibroblasts; Fibrosis; Future; Goals; Human; Hyperplasia; Immunohistochemistry; Implant; In Vitro; Inflammatory; Intercellular adhesion molecule 1; Interleukin-6; Knowledge; Macrophage Inflammatory Protein-1; Mediating; Mediator of activation protein; Methods; Mission; Modeling; Monocyte Chemoattractant Protein-1; Morbidity - disease rate; Mus; Myocardial Infarction; Operative Surgical Procedures; 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; T-Lymphocyte; TNF gene; Testing; Tissues; Transgenic Organisms; United States National Institutes of Health; Ventricular; Work; Wound Healing; angiogenesis; base; disability; healing; improved; innovation; macrophage; monocyte chemoattractant protein 1 receptor; mortality; mouse model; neutralizing antibody; neutrophil; novel therapeutics; public health relevance; receptor

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（由申请人提供）：目前脑动脉瘤（CA）的治疗方法是夹闭或弹簧圈栓塞。弹簧圈似乎比夹闭更安全，但与动脉瘤复发率显着相关，并且需要让患者再次接受治疗。已发表的研究结果表明，成功治愈且不会复发的动脉瘤的特征是含有巨噬细胞、结缔组织增殖、成纤维细胞、胶原蛋白、平滑肌细胞和血管生成的组织向内生长。我们的研究表明，植入小鼠动脉瘤的 MCP-1 释放弹簧圈可产生比标准铂弹簧圈多 25% 的动脉瘤组织向内生长。然而，关于动脉瘤愈合的机制，特别是 MCP-1 的作用，在知识上还存在根本性的差距。本申请的目的是通过定义 MCP-1 在动脉瘤愈合中的作用、机制和下游介质来填补这一知识空白。根据我们的初步结果，中心假设是 MCP-1 对于动脉瘤愈合是必需的，动脉瘤愈合由细胞特异性群体引导并受下游介质调节，以在动脉瘤管腔中产生组织向内生长。中心假设将通过新研究者发起的拨款申请的三个目标进行测试： 假设 I：MCP-1 对于动脉瘤愈合是必要的，并在动脉瘤部位局部发挥作用。目标1A。证明并交叉验证 MCP-1 对于动脉瘤愈合是必要的。目标 1B。展示 MCP-1 在动脉瘤愈合中的局部作用与全身作用。假设 II：MCP-1 介导的动脉瘤愈合是由循环和常驻细胞特异性群体以明确的顺序方式指导的。目标2A。定义指导 MCP-1 介导的动脉瘤愈合的细胞特异性群体的时间序列。瞄准2B。确定指导 MCP-1 介导的动脉瘤愈合的细胞特异性细胞群的来源（循环细胞与驻留细胞）。假设III：MCP-1介导的动脉瘤愈合受到下游介质的调节。瞄准3A。定义 MCP-1 介导的动脉瘤愈合的下游介质。瞄准3B。展示下游介质对 MCP-1 介导的动脉瘤愈合的调节。瞄准3C。交叉验证人类动脉瘤标本中的下游介质。所提出的应用具有创新性，因为：1）我们的小鼠颈动脉瘤模型； 2）一种在小鼠颈动脉瘤模型中进行血管造影的新方法； 3）我们的涂层线圈的方法，以持续释放介质以局部递送至动脉瘤； 4）我们重点了解MCP-1的机制； 5)使用人类动脉瘤标本。这项工作意义重大，因为它可以直接翻译并交付给患者。一旦我们在小鼠模型中建立了机制，未来的方向将在兔子动脉瘤模型中进行测试，这是人体试验的直接先驱。