? 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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL062289-14
Application #
8282830
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Gao, Yunling
Project Start
1999-05-01
Project End
2013-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
14
Fiscal Year
2012
Total Cost
$520,531
Indirect Cost
$206,011
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Chen, Pei-Yu; Simons, Michael (2016) When endothelial cells go rogue. EMBO Mol Med 8:1-2
Simons, Michael; Eichmann, Anne (2015) Molecular controls of arterial morphogenesis. Circ Res 116:1712-24
Ju, Rong; Zhuang, Zhen W; Zhang, Jiasheng et al. (2014) Angiopoietin-2 secretion by endothelial cell exosomes: regulation by the phosphatidylinositol 3-kinase (PI3K)/Akt/endothelial nitric oxide synthase (eNOS) and syndecan-4/syntenin pathways. J Biol Chem 289:510-9
Baeyens, Nicolas; Mulligan-Kehoe, Mary Jo; Corti, Federico et al. (2014) Syndecan 4 is required for endothelial alignment in flow and atheroprotective signaling. Proc Natl Acad Sci U S A 111:17308-13
Corti, Federico; Finetti, Federica; Ziche, Marina et al. (2013) The syndecan-4/protein kinase Cα pathway mediates prostaglandin E2-induced extracellular regulated kinase (ERK) activation in endothelial cells and angiogenesis in vivo. J Biol Chem 288:12712-21
Ju, Rong; Simons, Michael (2013) Syndecan 4 regulation of PDK1-dependent Akt activation. Cell Signal 25:101-5
Elfenbein, Arye; Simons, Michael (2013) Syndecan-4 signaling at a glance. J Cell Sci 126:3799-804
Lanahan, Anthony; Zhang, Xi; Fantin, Alessandro et al. (2013) The neuropilin 1 cytoplasmic domain is required for VEGF-A-dependent arteriogenesis. Dev Cell 25:156-68
Atri, Deepak; Larrivée, Bruno; Eichmann, Anne et al. (2013) Endothelial signaling and the molecular basis of arteriovenous malformation. Cell Mol Life Sci :
Moraes, Filipa; Paye, Julie; Mac Gabhann, Feilim et al. (2013) Endothelial cell-dependent regulation of arteriogenesis. Circ Res 113:1076-86

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