In the United States, unruptured intracranial aneurysms are present in approximately 4-5% of the general population. Once diagnosed, appropriate therapy may be difficult to recommend with confidence. The choices are (1) open surgery to clip the aneurysm; (2) less invasive, imaging-guided navigation through vessels for placement of a device to occlude the aneurysm cavity; or, (3) observation. Surgery is curative, but carries a 17% risk of serious side effects. Endovascular placement of occlusion devices involves lower risk (5-7%), but suboptimal rates of permanent aneurysm closure; subsequent regrowth occurs in many cases. Observation carries a risk of rupture, which is fatal in the majority of cases and neurologically damaging to the majority of survivors. With the objective of altering the grim outlook just described for persons harboring unruptured intracranial aneurysms, work is proposed to achieve three important goals to further aneurysm research: 1) to validate of a new animal model of human aneurysms; 2) to probe the complex interaction between aneurysm hemodynamics and endothelial cell dysfunction, which may represent the initial trigger for rupture; and 3 ) to validate a new technique for processing both animal and human tissue bearing endovascular coils, and to demonstrate homology between the tissue reaction in rabbits and humans. These goals can be effectively addressed at this time because of the introduction with this program of two major advances in the infrastructure for neurovascular research: an animal model mimicking important characteristics of human intracranial aneurysms, and a new method for tissue processing that should allow, for the first time, routine evaluation of the biological response to implantation of occlusion devices. The specific research design progresses as follows: validation of the long-term behavior of the animal model; study of aneurysm hemodynamics and endothelial cell function; use of the animal model to confirm the utility of the new tissue-processing method; and, use of the method to compare cellular responses to the placement of therapeutic occlusion devices between animals and humans. This research program will (1) offer insight into the cellular mechanisms important in rupture of aneurysms, (2) advance groundwork necessary for improving the efficacy of minimally invasive therapy, and, (3) yield a robust, well-characterized animal model for use in further research developments to enhance health by preventing the catastrophic events resulting from spontaneous rupture of intracranial aneurysms.
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