Cerebral Cavernous Malformations (CCM) are leaky vascular lesions that cause hemorrhagic strokes, seizures, and neurological deficits. Familial CCM type 1 (fCCM1) is an autosomal dominant disease caused by mutations in the KRIT1 gene, and is typically characterized by multiple lesions on MRI that increase in number and size over time. Patients present with marked variability of disease burden, even among carriers of the same gene mutation, family or age. Currently only neurosurgical options are available to patients, although recent data from CCM animal models show promising benefits of drugs that target RhoA (statins and fasudil) for stabilizing endothelial junctions and reducing vascular leakage. In this project, we will leverage our considerable efforts over the past 5 years to recruit, phenotype, and identify modifiers of CCM disease severity in fCCM1 patients with the same founder mutation (Q455X), known as the Common Hispanic Mutation (CHM). Our long-term goal is to identify biomarkers for disease severity, which could aid in identifying patients at high risk for hemorrhage who would benefit most from pharmacologic therapy, and sets the stage for future clinical treatment trials. In the next funding period, we will continue longitudinal follow-up of 300 CCM1-CHM cases to ascertain outcomes and better understand the natural history of the disease, build on our existing genome wide association data to investigate the role of inflammation in CCM, and expand our focus on biomarker development for clinical trials, including gene expression and neuroimaging biomarkers. We will recruit a replication cohort of 300 fCCM1 cases caused by CHM and other CCM1 gene mutations to assess generalizability of findings in the CCM1-CHM cohort, and collect new data for follow-up studies (including plasma and serum samples, and surgically resected tissue specimens). We propose the following aims:
Aim 1 : To longitudinally characterize the phenotypic expression and natural history of CCM1-CHM patients.
Aim 2 : To investigate the role of inflammation in CCM1 disease progression.
Aim 3 : To develop biomarkers predictive of disease severity and progression for medical treatment of CCM.
Genetic forms of cerebral cavernous malformations are characterized by multiple cavernous malformations of the central nervous system with marked variability of disease severity among affected patients based on hemorrhage, new lesion formation and growth overtime. This large, well-characterized cohort of CCM1 patients provides the opportunity to identify modifiers of disease severity and biomarker development.
|Wellman, Rebecca J; Cho, Su Bin; Singh, Pratibha et al. (2018) G?q and hyper-phosphorylated ERK expression in Sturge-Weber syndrome leptomeningeal blood vessel endothelial cells. Vasc Med :1358863X18786068|
|Morrison, Melanie A; Payabvash, Seyedmehdi; Chen, Yicheng et al. (2018) A user-guided tool for semi-automated cerebral microbleed detection and volume segmentation: Evaluating vascular injury and data labelling for machine learning. Neuroimage Clin 20:498-505|
|Walcott, Brian P; Winkler, Ethan A; Zhou, Sirui et al. (2018) Identification of a rare BMP pathway mutation in a non-syndromic human brain arteriovenous malformation via exome sequencing. Hum Genome Var 5:18001|
|Pawlikowska, Ludmila; Nelson, Jeffrey; Guo, Diana E et al. (2018) Association of common candidate variants with vascular malformations and intracranial hemorrhage in hereditary hemorrhagic telangiectasia. Mol Genet Genomic Med 6:350-356|
|De la Torre, Alejandro J; Luat, Aimee F; Juhász, Csaba et al. (2018) A Multidisciplinary Consensus for Clinical Care and Research Needs for Sturge-Weber Syndrome. Pediatr Neurol 84:11-20|
|Meybodi, Ali Tayebi; Kim, Helen; Nelson, Jeffrey et al. (2018) Surgical Treatment vs Nonsurgical Treatment for Brain Arteriovenous Malformations in Patients with Hereditary Hemorrhagic Telangiectasia: A Retrospective Multicenter Consortium Study. Neurosurgery 82:35-47|
|Kasthuri, Raj S; Montifar, Megan; Nelson, Jeffrey et al. (2017) Prevalence and predictors of anemia in hereditary hemorrhagic telangiectasia. Am J Hematol :|
|Zou, Xiaowei; Hart, Blaine L; Mabray, Marc et al. (2017) Automated algorithm for counting microbleeds in patients with familial cerebral cavernous malformations. Neuroradiology 59:685-690|
|Tang, Alan T; Choi, Jaesung P; Kotzin, Jonathan J et al. (2017) Endothelial TLR4 and the microbiome drive cerebral cavernous malformations. Nature 545:305-310|
|Strickland, Corinne D; Eberhardt, Steven C; Bartlett, Mary R et al. (2017) Familial Cerebral Cavernous Malformations Are Associated with Adrenal Calcifications on CT Scans: An Imaging Biomarker for a Hereditary Cerebrovascular Condition. Radiology 284:443-450|
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