Angela J. Glading, Ph.D.
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Contact
University of Rochester
School of Medicine and Dentistry
601 Elmwood Ave, Box 711
Rochester, New York 14642
Office: 585 273-5750 (primary)
Lab: 585 273-3043
Fax: 585 273-2652
Research in the Glading lab focuses on the role of cell-cell contact in regulating cellular function in both the normal and disease state. Specifically, we are interested in studying the molecular mechanisms that regulate the integrity and growth of blood vessels. A second major focus of the lab is the regulation of cell-cell contacts between epithelial cells, and how those contacts are disrupted during tumor growth and metastasis. We use cell culture and animal models to investigate specific signaling pathways involved in these processes.
Our research is currently focused on a new family of proteins that we have identified as regulators of cell-cell contact. The CCM proteins are scaffolding proteins that organize an intracellular complex at the cell-cell junction. Loss of any of the CCM proteins (KRIT1 (also called CCM1), CCM2 (malcavernin/OSM), and CCM3 (PDCD10)) leads to the development of Cerebral Cavernous Malformation (CCM), a type of vascular malformation found in 0.1-0.5% of the population. This disease is characterized by the development of focal areas of abnormal capillary growth within the brain and other tissues. CCM lesions consist of beds of dilated, leaky blood vessels, with defective endothelial cell-cell junctions. Symptoms include seizure, cerebral hemorrhage and focal neurological deficits, likely due to blood leakage from the lesion into the surrounding tissue.
Of the CCM proteins, we identified KRIT1 as a component of cell-cell junctions, where it interacts with structural and signaling proteins to regulate the stability of the junction. KRIT1 was first identified as a binding partner of the GTPase Rap1a, and we have shown that KRIT1 is the Rap1 effector responsible for the ability of active Rap1 to stabilize endothelial cell-cell adhesion. Loss of KRIT1 directly contributes to permeability and vascular leak by inhibiting the association of beta- and p120-catenin with VE-cadherin, and by altering the activity of Rho family GTPases. Finally, loss of KRIT1, by de-stabilizing cell-cell adhesion, promotes the localization of beta-catenin to the nucleus, where it modulates gene expression. However, many questions remain unanswered including; 1) what are the mechanisms that regulate KRIT1 signaling in normal cells? and 2) how does KRIT1 signaling contribute to changes in cellular behavior?
Although CCM is type of vascular malformation, KRIT1 is a ubiquitous protein, and our evidence indicates that it regulates cell-cell contacts in many types of cells. As the dynamic regulation of cell-cell contact, including beta-catenin signaling, is important for tissue maintenance and growth, the outcome of this research has the potential to impact a wide range of scientific fields. For example, our data indicate that KRIT1 functions as a tumor suppressor in epithelial cells, a novel function for this family of proteins. Our exciting studies continue to explore the molecular mechanism(s) behind this newly described function, as well as probe the contribution of KRIT1 signaling to the pathogenesis of other diseases reliant on vascular leak and beta-catenin signaling, such as arthritis.
Current Appointments
- Assistant Professor - Department of Pharmacology and Physiology (SMD)
| Education | ||
|---|---|---|
| Ph.D. Cellular and Molecular Pathology | University of Pittsburgh | 2002 |
| BS Biochemistry and Biology | Whitworth College | 1997 |
| Post-Doctoral Training & Residency | |
|---|---|
| Department of Medicine, University of California San Diego, Supervisor: Mark H. Ginsberg | 2004 - 2008 |
| Department of Cell Biology, The Scripps Research Institute, Supervisor: Mark H. Ginsberg | 2002 - 2004 |
| Fellowship Awards | |
|---|---|
| American Cancer Society Post-doctoral Fellowship | 2004 - 2007 |
