Knock them down! Therapeutic targeting of RIP kinases to treat cardiometabolic diseases

Dr Denuja Karunakaran, University of Ottawa Heart Institute, Canada

Chronic activation of the innate immune system drives inflammation and contributes directly to atherosclerosis, obesity and insulin resistance. RIP kinases (RIPK) are members of the serine/threonine family of kinases that have recently been shown to play an important role in cell death. We have previously shown that necroptosis, a pro-inflammatory form for programmed cell death, is activated in the vessel wall and drives atherosclerosis via activation of RIPK3 and its downstream target, MLKL. Here, we sought to determine upstream regulators of necroptosis in atherosclerosis and metabolic disease, and hypothesized that RIPK1, a key regulatory kinase upstream of NF-kB activation, apoptosis and necroptosis, drives immune cell inflammation in cardiometabolic diseases. Our studies identify a novel role for RIPK1 gene expression in atherosclerosis and obesity, and therapeutic knockdown of RIPK1 reduces disease progression. This seminar will explore the intricate yet distinct mechanisms by which genetic regulation of RIPK1 drives early atherosclerosis and diet-induced obesity.

Dr Denuja Karunakaran is currently an Associate Scientist at the University of Ottawa Heart Institute (UOHI), Canada. She completed her B. Biomed. Sci. (Hons) and PhD in human platelet biology at Monash University, Australia. She then pursued the prestigious Heart Foundation Postdoctoral Fellowship at the University of New South Wales, Australia, followed by an Endowed Cardiovascular Genetics Postdoctoral Fellowship at UOHI. Her research interests include RIP kinases and microRNAs in inflammation, cell death and efferocytosis in coronary artery disease driven by psoriasis, thrombosis and obesity. Dr Karunakaran is a recent recipient of National Psoriasis Foundation Early Career Grant.

In recognition of her research contributions, Dr. Karunakaran has been awarded the 2017 American Society for Investigative Pathology (ASIP) Experimental Pathologist-in-Training Award, American Heart Association 2017 ATVB Council Early Career Investigator Finalist & 2018 Peter Dundley White International Scholar Awards, and The University of Ottawa Heart Institute 2016 Cardiovascular Research Trainee of the Year. She is also an early career member on the ATVB journal editorial board.