? 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.
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