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

描述（由申请人提供）：目前治疗脑动脉瘤（CA）的方法是夹闭或卷曲。卷取术似乎比夹持术更安全，但与动脉瘤复发率显著相关，患者需要退行手术。已发表的研究结果表明，成功愈合的动脉瘤不复发的特征是组织内生长含有巨噬细胞、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，mcp -1释放线圈植入小鼠动脉瘤后，产生的动脉瘤组织长入比标准铂线圈大25%。然而，关于动脉瘤愈合的机制，特别是MCP-1的作用，在知识上存在根本性的差距。本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空白。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，这是由细胞特异性群体指导并由下游介质调节的，从而在动脉瘤腔内产生组织长入。该中心假设将根据新研究者发起的资助申请的三个目标进行验证：假设1:MCP-1是动脉瘤愈合所必需的，并在动脉瘤部位局部起作用。目的1。证明并交叉验证MCP-1对于动脉瘤愈合是必要的。目标1 b。证明MCP-1在动脉瘤愈合中的局部作用与全身作用。假设二：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2。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2 b。确定指导mcp -1介导的动脉瘤愈合的细胞特异性群体（循环与常驻）的来源。假设三：mcp -1介导的动脉瘤愈合受下游介质调节。目标3。确定MCP- 1介导的动脉瘤愈合的下游介质。目标3 b。证明下游介质对mcp -1介导的动脉瘤愈合的调节。目标3 c。交叉验证人类动脉瘤标本中的下游介质。该应用具有创新性，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的新方法；3)我们的方法涂层线圈缓释介质局部输送到动脉瘤；4)重点了解MCP-1的作用机制；5)使用人动脉瘤标本。这项工作意义重大，因为它可以直接翻译并交付给患者。未来的方向是，一旦我们在小鼠模型中建立了机制，我们将在兔子动脉瘤模型中进行测试，这是人类试验的直接先驱。

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.