Angela Glading, Ph.D.
Department of Pharmacology and Physiology
University of Rochester
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, particularly in context of vascular development and vessel biology.
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. Changes in this barrier regulate the normal immune response and contribute to the growth of new vessels. We use in vitro and in vivo approaches to investigate how barrier function impacts vessel growth and morphology. To do this, we have capitalized on the requirement for the scaffolding proteins CCM1/KRIT1, CCM2, and CCM3 for effective barrier function. Mutations in these proteins lead to the development of Cerebral Cavernous Malformations (CCM) a type of vascular malformation found in 0.05% of the population. This complex disease provides a compelling context for understanding the consequence of loss of endothelial cell-cell contact on endothelial behavior and vessel integrity in vitro and in vivo. We have used KRIT1 deficient endothelial cells (siRNA, CRISPR) and tissues (KRIT1 knockout and KRIT1 endothelial-specific knockout mice) as models 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gene expression (Glading, 2010), induces vascular permeability in vivo (Corr et al, 2012), and promotes angiogenesis (unpublished data), as just a few examples.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.
Laboratory Website: https://www.urmc.rochester.edu/people/27315903-angela-glading
Members of the laboratory:
Harsha Swamy (graduate student)
Nick Nobiletti (graduate student)
Samantha Colayori (lab manager)
Olivia Matvey (undergraduate student)
- Microvascular Mimetics for the Study of Leukocyte-Endothelial Interactions. Khire TS, Salminen AT, Swamy H, Lucas KS, McCloskey MC, Ajalik RE, Chung HH, Gaborski TR, Waugh RE, Glading AJ, McGrath JL. Cell Mol Bioeng. 2020 Jan 31;13(2):125-139. doi: 10.1007/s12195-020-00611-6. eCollection 2020 Apr.
- VEGF signalling enhances lesion burden in KRIT1 deficient mice. DiStefano PV, Glading AJ. J Cell Mol Med. 2020 Jan;24(1):632-639. doi: 10.1111/jcmm.14773.
- Disease models in cerebral cavernous malformations. Glading AJ, Finetti F, Trabalzini L. Drug Disc Today: Dis Mod. 2019, in press https://doi.org/10.1016/j.ddmod.2019.10.009.