Cerebral cavernous malformation (CCM) is a hereditary vascular disorder that results in the formation of dilated, leaky capillaries in the central nervous system of affected individuals. Patients with CCM suffer from seizures, migraines, focal neurological deficits, and stroke. Loci for CCM have been mapped to three genes, two of which encode scaffolding proteins that facilitate the localization and activation of the MAPK-kinase- kinase MEKK3 at sites of actin reorganization. This observation suggests the hypothesis that CCM is caused by inappropriate regulation of MEKKS-associated signaling networks. This hypothesis is further supported by the finding that targeted disruption of MEKK3 and its downstream targets, p38 and ERK5 all result in embryonic lethality due to defects in vascular morphogenesis. This proposal will investigate the role of the CCM proteins in the spatial and temporal regulation of MEKK3 and its downstream kinases. An in vitro model of astrocyte-endothelial cell interactions will be used to test the hypothesis that the CCM proteins regulate intercellular signals required for vascular homeostasis in the nervous system. This research will lend insight into the function of scaffolding proteins as coordinators of the spatial and temporal activation of signaling networks and their role in vascular physiology and disease. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32HL084971-01
Application #
7112699
Study Section
Special Emphasis Panel (ZRG1-F10-H (20))
Program Officer
Meadows, Tawanna
Project Start
2006-05-15
Project End
2009-05-14
Budget Start
2006-05-15
Budget End
2007-05-14
Support Year
1
Fiscal Year
2006
Total Cost
$43,996
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Pharmacology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Hilder, Thomas L; Malone, Michael H; Bencharit, Sompop et al. (2007) Proteomic identification of the cerebral cavernous malformation signaling complex. J Proteome Res 6:4343-55
Malone, Michael H; Sciaky, Noah; Stalheim, Lisa et al. (2007) Laser-scanning velocimetry: a confocal microscopy method for quantitative measurement of cardiovascular performance in zebrafish embryos and larvae. BMC Biotechnol 7:40