The cerebral cavernous malformation (CCM) is a common vascular anomaly, predisposing to a lifetime risk of stroke and other neurologic sequelae. Lesions occur in either a sporadic form or in an autosomal- dominant inherited form, the latter due to mutation in one of three genes. Molecular genetic analyses of surgically resected CCM lesions by the Awad and Marchuk laboratories has uncovered second-hit somatic CCM gene mutations in endothelial cells lining the vascular caverns, suggesting a two-hit mutational mechanism of CCM pathogenesis. Using this knowledge, we have developed robust animal models of CCM recapitulating the histology, molecular signatures and ultrastructure of the human lesions. Although we can now describe the major stages of lesion pathogenesis, the underlying molecular switches that modulate the progression of these stages remain unknown. In parallel work, the Ginsberg and other laboratories have shown that loss of CCM gene function impairs endothelial cell junctions, in part regulated by RhoA/ROCK activity. Yet, the Ginsberg, Kahn, and other laboratories have shown that loss of CCM function alters other major signaling pathways such as Notch, Wnt/-catenin, FOXO1, and KFL2/MEKK2 signaling. The centrality of RhoA/ROCK activity in CCM pathogenesis, and hence its optimal therapeutic target(s), remain unknown. Our central hypothesis of this P01 proposal is that the loss of CCM proteins contributes to lesion formation via multiple aberrant signaling pathways, some of which are RhoA/ROCK-independent. We further propose that different signaling and genetic aberrations modulate distinct stages of lesion development and maturation. We propose to analyze molecular genetic events during lesion development, and investigate associated signaling in vivo and in vitro. Our murine models enable us to investigate the role of these pathways in vivo at the different stages of CCM pathogenesis, and our collection of surgically resected CCMs allows us to validate these findings in the clinically relevant mature human lesion. The continuum of in vitro, in vivo and detailed analysis of mouse and human lesions will help us create an ordered scheme of aberrant signaling networks in relation to lesion pathogenesis, and translate new fundamental insights into rational therapeutic strategies for this disease.

Public Health Relevance

Cerebral Cavernous Malformations (CCM) are blood vessel abnormalities occurring in the brain. These CCMs can bleed and cause seizures or strokes. In this program project four leading laboratories working on this disease will study the genes and proteins that are known to cause CCM. Using mice that we have genetically engineered to have the disease, we will work towards a new therapy to reduce the bleeding in CCMs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
1P01NS092521-01
Application #
8932372
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Koenig, James I
Project Start
2015-09-01
Project End
2020-06-30
Budget Start
2015-09-01
Budget End
2016-06-30
Support Year
1
Fiscal Year
2015
Total Cost
$1,338,677
Indirect Cost
$180,541
Name
Duke University
Department
Genetics
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Lopez-Ramirez, Miguel Alejandro; Fonseca, Gregory; Zeineddine, Hussein A et al. (2017) Thrombospondin1 (TSP1) replacement prevents cerebral cavernous malformations. J Exp Med 214:3331-3346
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
Wetzel-Strong, Sarah E; Detter, Matthew R; Marchuk, Douglas A (2017) The pathobiology of vascular malformations: insights from human and model organism genetics. J Pathol 241:281-293
Gingras, Alexandre R; Puzon-McLaughlin, Wilma; Bobkov, Andrey A et al. (2016) Structural Basis of Dimeric Rasip1 RA Domain Recognition of the Ras Subfamily of GTP-Binding Proteins. Structure 24:2152-2162
Zhou, Zinan; Tang, Alan T; Wong, Weng-Yew et al. (2016) Cerebral cavernous malformations arise from endothelial gain of MEKK3-KLF2/4 signalling. Nature 532:122-6
de Kreuk, Bart-Jan; Gingras, Alexandre R; Knight, James Dr et al. (2016) Heart of glass anchors Rasip1 at endothelial cell-cell junctions to support vascular integrity. Elife 5:e11394
Girard, Romuald; Zeineddine, Hussein A; Orsbon, Courtney et al. (2016) Micro-computed tomography in murine models of cerebral cavernous malformations as a paradigm for brain disease. J Neurosci Methods 271:14-24
Lagarrigue, Frederic; Kim, Chungho; Ginsberg, Mark H (2016) The Rap1-RIAM-talin axis of integrin activation and blood cell function. Blood 128:479-87
Lagarrigue, Frederic; Vikas Anekal, Praju; Lee, Ho-Sup et al. (2015) A RIAM/lamellipodin-talin-integrin complex forms the tip of sticky fingers that guide cell migration. Nat Commun 6:8492
Zhou, Zinan; Rawnsley, David R; Goddard, Lauren M et al. (2015) The cerebral cavernous malformation pathway controls cardiac development via regulation of endocardial MEKK3 signaling and KLF expression. Dev Cell 32:168-80