Cerebral cavernous malformations (CCMs) are dilated and hemorrhagic capillaries that lose surrounding parenchymal cells and form multicavernous vascular lesions within the central nervous system. Conservative estimates suggest that 300,000 people have this disease within the United States. CCMs are caused by biallelic loss-of-function mutations within one of three different CCM genes and can occur sporadically or through an autosomal-dominant mode of inheritance. When CCMs become symptomatic, patients experience headache, seizure, focal neurologic deficits, recurrent hemorrhages, and stroke. No pharmaceutical therapeutic is available to treat CCMs; the only therapy is surgical resection. Although curative, these operations are invasive and limited by the anatomic location of the CCM; there is a large cohort of CCM patients for whom no therapy is available. Decades of research have focused on two stages of the disease: 1) the beginning - with in vitro and in vivo studies of CCM formation and 2) the end ? with severely symptomatic CCMs surgically resected from patients. What has eluded researchers is the ability to study CCM maturation between formation and the development of symptoms. This limitation is due to the lack of an animal model that can be induced to recapitulate the features of human CCMs and the lack of diversity within the human samples, since only the most severe and symptomatic CCMs are resected ? and only when absolutely necessary. The clinically relevant CCM features are multicavernous structure, hemorrhaging, and inflammatory infiltrate. The current inducible mouse model does not develop CCMs that hemorrhage or gain other important pathologic features. The CCM research community needs a mouse model that better recapitulates the human disease in order to gain greater insights into the disease course and begin to investigate the molecular pathways necessary for CCM maturation. The overall objective of this proposal is to gain fundamental knowledge of how CCMs mature and identify therapeutic interventions that disrupt CCM maturation and improve disease outcomes. I have developed a variation of the inducible mouse model that results in a novel phenotype of CCMs, dispersed throughout the brain, brainstem, and spinal cord, that develop and mature over a period of several weeks. Unlike the traditional inducible model, my model develops a subset of CCMs that hemorrhage and contain inflammatory infiltrates in the surrounding brain tissue. This model is a resource that provides an opportunity to systematically investigate a previously unstudied component of the disease and conduct the first studies to determine the role of specific molecular pathways in CCM maturation. Completion of the following Specific Aims will generate fundamental knowledge of CCM pathology and advance the field toward developing the first pharmacologic therapy for CCM patients:
Aim 1 : Determine the order in which CCMs acquire pathologic features during maturation Aim 2: Determine the role of increased ROCK activity and inflammatory infiltrates in CCM maturation
Occurring in approximately 0.1-0.5% of the general population, cerebral cavernous malformations (CCMs) are dilated and hemorrhagic capillaries within the central nervous system that cause headache, seizure, focal neurologic deficits, stroke, and death. Utilizing a novel mouse model, this proposal seeks to gain fundamental knowledge of a previously unstudied component of the disease ? CCM maturation. Elucidating how CCMs mature and become symptomatic will guide the development of more efficacious clinical interventions and contribute to the NHLBI?s mission to alleviate the burden of cardiovascular disease.