? PROJECT 3, MEKK3-ERK5-KLF signaling in CCM pathogenesis Cerebral cavernous malformation (CCM) is a common inherited cerebrovascular disease, and a major cause of stroke and neurologic deficit in younger individuals. Genetic studies in humans have shown that CCMs are caused by loss of three adaptor proteins (KRIT1, CCM2 and PDCD10) that function in a common signaling complex in the endothelial cells that line blood vessels. However, how this signaling complex prevents CCM formation is not known and there are presently no medical therapies to treat this neurovascular disease. We have used genetic studies in developing mice and fish to gain new insight into the downstream mechanisms and effectors of CCM signaling in endothelial cells in vivo. Our studies in the developing heart reveal a new and unexpected mechanism by which CCM signaling regulates endothelial gene expression through effects on the MEKK3 MAPK cascade and the KLF transcription factors. Our studies demonstrate this regulatory mechanism to be causal for the developmental defects associated with endothelial loss of the CCM pathway, and similar gene expression changes are seen in CCM-deficient endothelial cells in the brain. This proposal will extend these developmental studies to test whether increased MEKK3-ERK5-KLF signaling also underlies CCM formation in the brain. To accomplish this we will (i) examine MEKK3-ERK5-KLF signaling in human and mouse CCMs, (ii) test whether genetic or pharmacologic manipulation of MEKK3-ERK5-KLF signaling can rescue of CCM formation in mice, and (iii) determine whether changes in this MAPK pathway underlie the many other signaling abnormalities described in CCMs and CCM-deficient endothelial cells. Our studies will complement those of Projects 1 and 2 and enable us to fully understand the genetic basis of CCM pathogenesis and the primary signaling abnormalities that underlie CCM formation, key steps in the development of new therapies for this disease.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Program Projects (P01)
Project #
Application #
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Duke University
United States
Zip Code
Klann, Jane E; Kim, Stephanie H; Remedios, Kelly A et al. (2018) Integrin Activation Controls Regulatory T Cell-Mediated Peripheral Tolerance. J Immunol 200:4012-4023
Detter, Matthew R; Snellings, Daniel A; Marchuk, Douglas A (2018) Cerebral Cavernous Malformations Develop Through Clonal Expansion of Mutant Endothelial Cells. Circ Res 123:1143-1151
Sun, Hao; Lagarrigue, Frederic; Gingras, Alexandre R et al. (2018) Transmission of integrin ?7 transmembrane domain topology enables gut lymphoid tissue development. J Cell Biol 217:1453-1465
Zeineddine, Hussein A; Girard, Romuald; Saadat, Laleh et al. (2018) Phenotypic characterization of murine models of cerebral cavernous malformations. Lab Invest :
Lagarrigue, Frederic; Gingras, Alexandre R; Paul, David S et al. (2018) Rap1 binding to the talin 1 F0 domain makes a minimal contribution to murine platelet GPIIb-IIIa activation. Blood Adv 2:2358-2368
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
Ye, Feng; Yang, Chansik; Kim, Jiyoon et al. (2017) Epigallocatechin gallate has pleiotropic effects on transmembrane signaling by altering the embedding of transmembrane domains. J Biol Chem 292:9858-9864
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
Lagarrigue, Frederic; Gertler, Frank B; Ginsberg, Mark H et al. (2017) Cutting Edge: Loss of T Cell RIAM Precludes Conjugate Formation with APC and Prevents Immune-Mediated Diabetes. J Immunol 198:3410-3415

Showing the most recent 10 out of 18 publications