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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL065648-09
Application #
8470209
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Reid, Diane M
Project Start
2000-09-01
Project End
2014-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
9
Fiscal Year
2013
Total Cost
$353,142
Indirect Cost
$96,663
Name
University of Utah
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
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