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

描述（由申请方提供）：目前脑动脉瘤（CA）的治疗方法是夹闭或弹簧圈栓塞。弹簧圈栓塞术似乎比夹闭术更安全，但与动脉瘤复发率显著相关，需要让患者再次住院。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的组织向内生长、结缔组织增生、成纤维细胞、胶原蛋白、平滑肌细胞和血管生成。我们的研究表明，MCP-1释放弹簧圈植入小鼠动脉瘤产生动脉瘤组织向内生长，比标准铂弹簧圈大25%。然而，关于动脉瘤愈合的机制，特别是MCP-1的作用，存在根本性的知识空白。本申请的目的是通过定义MCP-1在动脉瘤愈合中的作用、机制和下游介质来解决这一知识缺口。基于我们的初步结果，中心假设是MCP-1是动脉瘤愈合所必需的，动脉瘤愈合由细胞特异性群体指导并由下游介质调节，以在动脉瘤腔内产生组织向内生长。中心假设将通过新研究者发起的资助申请的三个目标进行测试：假设I：MCP-1是动脉瘤愈合所必需的，并在动脉瘤部位局部起作用。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。证明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驻留细胞特异性群体以确定的顺序方式指导的。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。目标2B确定指导MCP-1介导的动脉瘤愈合的细胞特异性群体（循环与驻留）的来源。假设III：MCP-1介导的动脉瘤愈合受下游介质调节。目标3A。定义MCP- 1介导的动脉瘤愈合的下游介质。目标3B证明下游介质对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样本中的下游介质。所提出的应用是创新性的，因为：1）我们的鼠颈动脉瘤模型; 2）在我们的鼠颈动脉瘤模型中进行血管造影术的新方法; 3）我们用于涂覆弹簧圈以持续释放介质以局部递送至动脉瘤的方法; 4）我们专注于理解MCP-1的机制;以及5）使用人动脉瘤标本。这项工作是重要的，因为它是直接翻译和交付给病人。一旦我们在小鼠模型中建立了机制，未来的方向将是在兔动脉瘤模型中进行测试，这是人体试验的直接先驱。

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.