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 1 A. Demonstrate and cross-validate MCP-1 is necessary for aneurysm healing.
Aim 1 B. 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 2 A. Define the temporal sequence of cell-specific populations that direct MCP-1-mediated aneurysm healing.
Aim 2 B. 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 3 A. Define the downstream mediators of MCP- 1-mediated aneurysm healing.
Aim 3 B. Demonstrate regulation of MCP-1-mediated aneurysm healing by downstream mediators.
Aim 3 C. 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.
The proposed research is relevant to the public health because up to 5% of the population has a cerebral aneurysm (CA); when they rupture, 50% of people die and 30% are dependent; and current treatments are associated with up to 31% morbidity and mortality for ruptured CAs, and 13% morbidity and mortality for unruptured CAs. Defining the role, mechanisms, and downstream mediators of MCP-1 in CA healing will enable the development of much-needed novel therapies (endovascular or drugs) to augment and accelerate CA healing for safer and better outcomes for CA patients, which is relevant to the part of NIH's mission that pertains to developing fundamental knowledge that will help to reduce the burdens of human disability.
|Hosaka, Koji; Rojas, Kelley; Fazal, Hanain Z et al. (2017) Monocyte Chemotactic Protein-1-Interleukin-6-Osteopontin Pathway of Intra-Aneurysmal Tissue Healing. Stroke 48:1052-1060|