Loss-of-function mutations in two genes, KRIT1 and OSM, cause Cerebral Cavernous Malformations (CCM). Despite the identification of the genetic basis for familial CCM, the function of these genes in vascular biology and disease are largely unexplored. OSM is most extensively studied and encodes an intracellular protein that is essential for mammalian cells to cope with physiologic stress. Our preliminary studies indicate that OSM and KRIT1 are critical scaffold proteins that regulate the response of endothelial cell-cell interactions to permeability factors and other stresses via a JNK kinase pathway.
Specific Aim 1) Determine whether KRIT1 and OSM genes mediate developmental angiogenesis through an endothelial autonomous mechanism. These studies seek to establish that OSM and KRIT1 play critical roles in a common intracellular endothelial signaling pathway required for angiogenesis.
Specific Aim 2) Investigate whether OSM and KRIT1 are endothelial scaffold proteins that regulate the integrity of endothelial cell-cell junction via a JNK-dependent pathway. We will examine whether OSM and KRIT1 forms an intracellular scaffold for an endothelial signaling complex that regulates JNK and curbs endothelial leak induced by vascular permeability factors and inflammatory cytokines.
Specific Aim 3) Understand the mechanism of endothelial barrier dysfunction in OSM and KRIT1 deficient mice. We will test a model of CCM pathogenesis whereby a primary defect in endothelial tight junctions predisposes the cerebral vascular bed to inflammation and leak. At the conclusion of these studies, we hope our contribution will be the elucidation of a new intracellular signaling pathway regulating endothelial cell-cell interaction and provide one of the first examples of a hereditary cerebral vascular disease being caused by a primary defect in pathways that regulate endothelial barrier function.
At the conclusion of our studies, we hope our contribution will be the elucidation of new intracellular signaling mechanisms regulating endothelial cell-cell interaction and the demonstration that hereditary cerebral vascular disease can be caused by a primary defect in molecular pathways that regulate endothelial barrier function.
| 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 |
| 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 |
| 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 |
| 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 |
| Drakos, Stavros G; Kfoury, Abdallah G; Hammond, Elizabeth H et al. (2010) Impact of mechanical unloading on microvasculature and associated central remodeling features of the failing human heart. J Am Coll Cardiol 56:382-91 |
| 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 |
| Li, Dean Y; Whitehead, Kevin J (2010) Evaluating strategies for the treatment of cerebral cavernous malformations. Stroke 41:S92-4 |
| 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 |
| Whitehead, Kevin J; Chan, Aubrey C; Navankasattusas, Sutip et al. (2009) The cerebral cavernous malformation signaling pathway promotes vascular integrity via Rho GTPases. Nat Med 15:177-84 |
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