Syndecan Function in Endothelial Cells

Yale University, New Haven CT

Investigators

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Abstract

Abstract¿ In¿the¿previous¿funding¿cycle¿we¿have¿demonstrated¿that¿syndecan?4¿,¿a¿transmembrane¿heparan¿sulfate? carrying¿core¿protein,¿plays¿two¿important¿signaling¿roles¿in¿endothelial¿cells:¿regulation¿of¿Akt¿activity¿via¿ control¿of¿mTOR¿complex¿2¿(mTORC2)¿assembly,¿and¿regulation¿of¿Rac1¿activation.¿Both¿Akt¿and¿Rac1¿are¿key¿ regulators¿of¿cell¿migration,¿proliferation¿and¿survival.¿In¿addition,¿Akt¿is¿involved¿in¿regulation¿of¿ angiogenesis¿while¿Rac¿plays¿an¿important¿role¿in¿shear¿stress¿response¿and¿regulation¿of¿vascular¿ permeability.¿The¿unexpected¿involvement¿of¿syndecan?4¿signaling¿in¿regulation¿of¿both¿of¿theses¿processes¿ places¿it¿squarely¿in¿the¿center¿of¿two¿major¿signaling¿networks¿and¿suggests¿an¿important¿role¿for¿this¿gene¿in¿ key¿biological¿processes.¿ ¿ In¿studies¿outlined¿in¿this¿application¿we¿propose¿to¿explore¿in¿depth¿the¿role¿of¿syndecan?4¿in¿regulation¿of¿ these¿signaling¿pathways¿establishing¿both¿the¿molecular¿basis¿of¿syndecan?4¿activity¿and¿functional¿ consequences¿of¿disruption¿of¿its¿expression¿including¿effects¿on¿normal¿and¿pathological¿angiogenesis,¿ arteriogenesis,¿and¿vascular¿permeability.¿¿Specifically,¿we¿propose¿the¿following¿three¿Aims:¿¿ 1)¿molecular¿basis¿of¿syndecan?4¿dependent¿regulation¿of¿mTOR¿activity;¿2)¿¿Functional¿significance¿of¿ syndecan?4?dependent¿regulation¿of¿mTOR¿activity¿and¿3)¿¿Syndecan?4¿dependent¿regulation¿of¿Rac1¿ activation.¿¿Taken¿together,¿these¿three¿Specific¿Aims¿will¿provide¿a¿comprehensive¿insight¿into¿the¿syndecan?4¿ role¿in¿regulation¿of¿endothelial¿biology¿and¿produce¿novel¿insights¿into¿control¿of¿mTOR/Akt¿and¿Rac¿ activities¿ Project Narrative Vascular health is an important medical issue relevant to a large spectrum of cardiovascular illnesses. This projects examines a functional role of a key molecule, syndecan-4, that regulates two key aspects of vascular biology; production of nitric oxide and cell replication and migration. A better understanding of syndecan-4 biology will directly contribute to therapeutic attempts at improving vascular health and developing treatments for cardiovascular diseases.