Research in the Griendling cardiovascular lab currently focuses on the physiopathology of the novel multifunctional protein Poldip2. Our initial in vitro studies showed that Poldip2 activates the NADPH oxidase Nox4 (Lyle 2009). More recently, using an in vivo knockdown model (Sutliff 2013), we found that Poldip2+/- mice are largely protected against brain edema and inflammation, following ischemic stroke (Hernandes 2018) or systemic LPS administration (Kikuchi 2019). Similarly, a substantial reduction in vascular leakage and inflammation is also observed in lung after systemic administration of LPS (Forrester 2019) or intratracheal instillation of P. aeruginosa in Poldip2+/- mice. Therefore, Poldip2 may become a novel therapeutic target in life-threatening diseases characterized by acute breakdown of endothelial and epithelial barriers, such as stroke and ARDS.
To verify this possibility, we have begun to investigate the therapeutic effects of drugs that reduce Poldip2 in vivo. However, the molecular mechanisms by which Poldip2 knockdown exerts its beneficial effects are still unknown. To begin answering this question, we recently conducted an RNA-seq experiment in cultured endothelial cells and found that Poldip2 downregulation with siRNA inhibits TNF-induced changes in gene expression.
We are now planning new in vivo experiments to determine which of those candidate molecular pathways are affected by Poldip2 genetic and pharmacologic knockdown. This work may lead to the future development of a new class of pharmacological agents: Poldip2 inhibitors, that would be used to stabilize tissue barriers, following injury or infection.
Contact Us
The Griendling lab is led by Kathy Griendling, PhD.
Dr. Griendling is the R. Wayne Alexander MD Professor of Medicine in the Division of Cardiology at Emory University and is also the vice chair for research and faculty development in the Emory University Department of Medicine.
Emory University
Division of Cardiology
1750 Haygood Dr. NE
Health Sciences Research Building II (HSRB II), Room N254
Atlanta, GA 30322