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.
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.
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| 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 |
| Zhu, Weiquan; London, Nyall R; Gibson, Christopher C et al. (2012) Interleukin receptor activates a MYD88-ARNO-ARF6 cascade to disrupt vascular stability. Nature 492:252-5 |
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| Larrieu-Lahargue, Frederic; Welm, Alana L; Thomas, Kirk R et al. (2011) Netrin-4 activates endothelial integrin {alpha}6{beta}1. Circ Res 109:770-4 |
| Niebel, Björn; Weiche, Benjamin; Mueller, Alan L et al. (2011) A luminescent oxygen channeling biosensor that measures small GTPase activation. Chem Commun (Camb) 47:7521-3 |
| Chan, Aubrey C; Drakos, Stavros G; Ruiz, Oscar E et al. (2011) Mutations in 2 distinct genetic pathways result in cerebral cavernous malformations in mice. J Clin Invest 121:1871-81 |
| 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 |
| 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 |
| 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 |
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