Connexins as Potential Biomarkers and Therapeutic Targets for Vascular Malformation
Abstract
Blood vessels form during development through coordinated signaling between vascular endothelial cells (EC) and their adjacent cell neighbors. Inherited mutations that disrupt these signaling processes can lead to vascular malformations with profound consequences on vascular organization and function. In the rare congenital disease Hereditary Hemorrhagic Telangiectasia (HHT), loss-of-function mutations affecting the Alk1 cell surface receptor drives the appearance of disorganized vascular lesions prone to sudden, serious rupture. The goal of this study is to understand how Alk1 mutation may promote vascular malformation by dysregulating connexins (Cx), constituent proteins of vascular gap junctions that support direct cell-cell signaling of small electrochemical signals. In the first year of this study, we have made significant progress towards understanding this question. We have improved our understanding of how Cx expression is altered by Alk1 loss of-function and have developed (and are continuing to develop) key tools for manipulating connexin expression in primary endothelial cells, alone or in combination with Alk1-deficiency. We have performed studies to better understand the impact of dysregulated Cx expression on EC behavior, gap junctional coupling, and are currently assessing the impact on vascular lesion formation in a microphysiological model of HHT. Lastly, we have received institutional approval for a clinical study in collaboration with the UCLA HHT Center of Excellence to collect HHT patient samples to understand how variations in Cx gene sequence might impact clinical presentation of HHT in patients.
Document Details
- Document Type
- Technical Report
- Publication Date
- Mar 01, 2022
- Accession Number
- AD1169496
Entities
People
- Jennifer S. Fang
Organizations
- University of California, Irvine