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Angela Glading, Ph.D.

Contact Information

Phone Numbers

Office: (585) 273-5750

Fax: (585) 273-2652

Research Labs

Faculty Appointments

Biography

Research

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.

Credentials

Education

1997
BS | Whitworth College
Biochemistry and Biology

2002
Ph.D. | University of Pittsburgh
Cellular and Molecular Pathology

Post-doctoral Training & Residency

07/2004 - 04/2008
Department of Medicine, University of California San Diego, Supervisor: Mark H. Ginsberg

04/2002 - 07/2004
Department of Cell Biology, The Scripps Research Institute, Supervisor: Mark H. Ginsberg

Awards

2001
The Takashi Murachi Young Investigator Award
Sponsor: FASEB

Publications

Journal Articles

4/2020
Khire TS, Salminen AT, Swamy H, Lucas KS, McCloskey MC, Ajalik RE, Chung HH, Gaborski TR, Waugh RE, Glading AJ, McGrath JL. "Microvascular Mimetics for the Study of Leukocyte-Endothelial Interactions." Cellular and molecular bioengineering.. 2020 Apr 0; 13(2):125-139. Epub 2020 Jan 31.

1/2020
DiStefano PV, Glading AJ. "VEGF signalling enhances lesion burden in KRIT1 deficient mice." Journal of cellular and molecular medicine.. 2020 Jan 0; 24(1):632-639. Epub 2019 Nov 20.

2020
Nobiletti N, Glading AJ. "Isolation of Cerebral Endothelial Cells from CCM1/KRIT1 Null Mouse Brain." Methods in molecular biology.. 2020 2152:259-265.

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