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Angela Glading

TitleAssistant Professor
InstitutionSchool of Medicine and Dentistry
DepartmentPharmacology and Physiology
AddressUniversity of Rochester Medical Center
School of Medicine and Dentistry
601 Elmwood Ave, Box 711
Rochester NY 14642
Other Positions
TitleAssistant Professor
InstitutionSchool of Medicine and Dentistry
DepartmentBiomedical Engineering

 
 Awards And Honors
2001     The Takashi Murachi Young Investigator Award  | FASEB
 
 Overview
In order for normal cells to function, they must adhere to their immediate environment, which includes other cells and proteins. In return, cells receive both mechanical and chemical signals from their environment that are important for cellular processes such as migration, proliferation, and gene expression. Defective or improperly regulated adhesion is observed in a wide variety of human diseases, including the major killers cancer and cardiovascular disease.

Research in the Glading lab focuses on unraveling how cell adhesion signaling regulates cellular behavior.

Currently, our work concentrates on how cell-cell adhesion modulates cell growth and differentiation in both the normal and disease state. Our main experimental context is the endothelial cell and the intact blood vessel. Vessel function is reliant on the ability of vessels to maintain an effective barrier between the blood and tissue, which is primarily regulated at the level of the endothelial cell-cell contact (endothelial junctions). Changes in this barrier regulate the normal immune response and contribute to the growth of new vessels (angiogenesis).

Recently, we described KRIT1 as a scaffolding protein that nucleates a signaling complex at sites of endothelial cell-cell contact. In confluent endothelial cells, the KRIT1 complex associates with cell-cell contacts and is required for junctional stability downstream of active Rap1 (Glading et al 2007). KRIT1 also sits at the nexus of multiple signaling pathways, including the canonical beta-catenin pathway (Glading and Ginsberg, 2010), vascular-endothelial growth factor receptor (VEGFR) activation (DiStefano and Glading, in press), RhoA/Rho Kinase activity (Glading et al, 2007), and Notch signaling, which KRIT1 supports or modifies to promote a stable vascular barrier. Our ongoing research aims to understand cell-cell contact impacts global cell signaling by examining how KRIT1 signaling contributes to changes in cellular behavior.

We use KRIT1 deficient endothelial cells (siRNA, CRISPR) and tissues (KRIT1 knockout and KRIT1 endothelial-specific knockout mice) as models to probe the consequence of loss of endothelial cell-cell contact on endothelial behavior and vessel integrity in vitro and in vivo. By using genetic manipulation of KRIT1, we have been able to prove that loss of cell-cell contact stimulates broad changes in gene expression (Glading, 2010), induces vascular permeability in vivo (Corr et al, 2012), and promotes angiogenesis (unpublished data), as just a few examples. By combining molecular and biochemical examination of specific signaling mechanisms with real-time physiology, we are able to establish key signaling events as critical for normal vascular function. In current research, we are using this approach to explore the crosstalk between inflammatory signaling, angiogenesis and cell-cell contact in the relevant physiological contexts of vascular integrity and cancer.

 
 Selected Publications
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  1. Corr M, Lerman I, Keubel JM, Ronacher L, Misra R, Lund F, Sarelius IH, Glading AJ. Decreased krev interaction-trapped 1 expression leads to increased vascular permeability and modifies inflammatory responses in vivo. Arterioscler Thromb Vasc Biol. 2012 Nov; 32(11):2702-10.
    View in: PubMed
  2. Glading AJ, Ginsberg MH. Rap1 and its effector KRIT1/CCM1 regulate beta-catenin signaling. Dis Model Mech. 2010 Jan-Feb; 3(1-2):73-83.
    View in: PubMed
  3. Glading A, Han J, Stockton RA, Ginsberg MH. KRIT-1/CCM1 is a Rap1 effector that regulates endothelial cell cell junctions. J Cell Biol. 2007 Oct 22; 179(2):247-54.
    View in: PubMed
  4. Glading A, Koziol JA, Krueger J, Ginsberg MH. PEA-15 inhibits tumor cell invasion by binding to extracellular signal-regulated kinase 1/2. Cancer Res. 2007 Feb 15; 67(4):1536-44.
    View in: PubMed
  5. Krueger J, Chou FL, Glading A, Schaefer E, Ginsberg MH. Phosphorylation of phosphoprotein enriched in astrocytes (PEA-15) regulates extracellular signal-regulated kinase-dependent transcription and cell proliferation. Mol Biol Cell. 2005 Aug; 16(8):3552-61.
    View in: PubMed
  6. Satish L, Blair HC, Glading A, Wells A. Interferon-inducible protein 9 (CXCL11)-induced cell motility in keratinocytes requires calcium flux-dependent activation of mu-calpain. Mol Cell Biol. 2005 Mar; 25(5):1922-41.
    View in: PubMed
  7. Glading A, Bodnar RJ, Reynolds IJ, Shiraha H, Satish L, Potter DA, Blair HC, Wells A. Epidermal growth factor activates m-calpain (calpain II), at least in part, by extracellular signal-regulated kinase-mediated phosphorylation. Mol Cell Biol. 2004 Mar; 24(6):2499-512.
    View in: PubMed
  8. Chou FL, Hill JM, Hsieh JC, Pouyssegur J, Brunet A, Glading A, Uberall F, Ramos JW, Werner MH, Ginsberg MH. PEA-15 binding to ERK1/2 MAPKs is required for its modulation of integrin activation. J Biol Chem. 2003 Dec 26; 278(52):52587-97.
    View in: PubMed
  9. Shiraha H, Glading A, Chou J, Jia Z, Wells A. Activation of m-calpain (calpain II) by epidermal growth factor is limited by protein kinase A phosphorylation of m-calpain. Mol Cell Biol. 2002 Apr; 22(8):2716-27.
    View in: PubMed
  10. Glading A, Lauffenburger DA, Wells A. Cutting to the chase: calpain proteases in cell motility. Trends Cell Biol. 2002 Jan; 12(1):46-54.
    View in: PubMed
  11. Glading A, Uberall F, Keyse SM, Lauffenburger DA, Wells A. Membrane proximal ERK signaling is required for M-calpain activation downstream of epidermal growth factor receptor signaling. J Biol Chem. 2001 Jun 29; 276(26):23341-8.
    View in: PubMed
  12. Glading A, Chang P, Lauffenburger DA, Wells A. Epidermal growth factor receptor activation of calpain is required for fibroblast motility and occurs via an ERK/MAP kinase signaling pathway. J Biol Chem. 2000 Jan 28; 275(4):2390-8.
    View in: PubMed
  13. Shiraha H, Glading A, Gupta K, Wells A. IP-10 inhibits epidermal growth factor-induced motility by decreasing epidermal growth factor receptor-mediated calpain activity. J Cell Biol. 1999 Jul 12; 146(1):243-54.
    View in: PubMed
  14. Wells A, Gupta K, Chang P, Swindle S, Glading A, Shiraha H. Epidermal growth factor receptor-mediated motility in fibroblasts. Microsc Res Tech. 1998 Dec 1; 43(5):395-411.
    View in: PubMed

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