This is a renewal of a previous grant that focused on hereditary hemorrhagic telangiectasia (HHT). The original grant triggered discoveries that linked the pathogenesis of HHT to mechanisms of arterial-venous identify and defined new roles for guidance cues in neurovascular regeneration. Here, we will use the genetics of cerebral cavernous malformations (CCM) to piece together a novel endothelial signaling pathway critical for vascular development and the pathogenesis of CCM. Loss-of-function mutations in three genes, KRIT1 (CCM1), OSM (CCM2), and PDCD10 (CCM3) cause CCM. In preliminary studies, we have made considerable advances in understanding the basic biology surrounding KRIT1 and OSM. These insights lead us to speculate that PDCD10 participates in a signaling pathway that is critical for endothelial cell architecture and cell-cell interaction. Our model would suggest that when both copies of PDCD10 are ablated, endothelial cells are severely compromised and fail to initiate the first angiogenic event in development, formation of the branchial arch arteries. When only one copy of PDCD10 is lost, as is the case in human disease, endothelial tubes form, however, the integrity of their barrier in response to stress is compromised, resulting in vascular leak. By gaining insights into the basic biological pathways regulated by PDCD10, we hope to point the way to future therapies for CCM.

Public Health Relevance

We seek to determine whether Cerebral Cavernous Malformations is a genetic disease that disrupts signaling pathways critical for endothelial cell architecture and cell-cell interaction. The mechanistic studies proposed will result in examining new pharmacologic strategies for treating CCM, a disease that currently can only be treated by neurosurgical interventions.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Reid, Diane M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Utah
Internal Medicine/Medicine
Schools of Medicine
Salt Lake City
United States
Zip Code
Gibson, Christopher C; Zhu, Weiquan; Davis, Chadwick T et al. (2015) Strategy for identifying repurposed drugs for the treatment of cerebral cavernous malformation. Circulation 131:289-99
Mleynek, Tara M; Chan, Aubrey C; Redd, Michael et al. (2014) Lack of CCM1 induces hypersprouting and impairs response to flow. Hum Mol Genet 23:6223-34
Chan, Aubrey C; Li, Dean Y; Berg, Michel J et al. (2010) Recent insights into cerebral cavernous malformations: animal models of CCM and the human phenotype. FEBS J 277:1076-83
London, Nyall R; Zhu, Weiquan; Bozza, Fernando A et al. (2010) Targeting Robo4-dependent Slit signaling to survive the cytokine storm in sepsis and influenza. Sci Transl Med 2:23ra19
Smith, Matthew C P; Li, Dean Y; Whitehead, Kevin J (2010) Mechanisms of vascular stability and the relationship to human disease. Curr Opin Hematol 17:237-44
Jones, Christopher A; Nishiya, Naoyuki; London, Nyall R et al. (2009) Slit2-Robo4 signalling promotes vascular stability by blocking Arf6 activity. Nat Cell Biol 11:1325-31