Laboratoire de recherche sur l’inflammation et le métabolisme vasculaires

Voir la liste des publications dans PubMed.

Publications choisies :

• Raggi P, Genest J, Giles JT, Rayner KJ, Dwivedi G, Beanlands RS, Gupta M. Atherosclerosis. 2018 Sep;276:98-108. Role of inflammation in the pathogenesis of atherosclerosis and therapeutic interventions
• Nguyen MA, Karunakaran D, Geoffrion M, Cheng HS, Tandoc K, Perisic Matic L, Hedin U, Maegdefessel L, Fish JE, Rayner KJ. Arterioscler Thromb Vasc Biol. 2018 Jan;38(1):49-63. Extracellular Vesicles Secreted by Atherogenic Macrophages Transfer MicroRNA to Inhibit Cell Migration.
• Rayner KJ. Arterioscler Thromb Vasc Biol. 2017 Jul;37(7):e75-e81. doi: 10.1161/ATVBAHA.117.309229. Review. Cell Death in the Vessel Wall: The Good, the Bad, the Ugly.
• Karunakaran D, Geoffrion M, Wei L, Gan W, Richards L, Shangari P, DeKemp EM, Beanlands RA, Perisic L, Maegdefessel L, Hedin U, Sad S, Guo L, Kolodgie FD, Virmani R, Ruddy T, Rayner KJ. Sci Adv. 2016 Jul 22;2(7):e1600224. doi: 10.1126/sciadv.1600224. eCollection 2016 Jul. Targeting macrophage necroptosis for therapeutic and diagnostic interventions in atherosclerosis.
• Karunakaran D, Thrush AB, Nguyen MA, Richards L, Geoffrion M, Singaravelu R, Ramphos E, Shangari P, Ouimet M, Pezacki JP, Moore KJ, Perisic L, Maegdefessel L, Hedin U, Harper ME, Rayner KJ. Circ Res. 2015 Jul 17;117(3):266-78. Macrophage Mitochondrial Energy Status Regulates Cholesterol Efflux and Is Enhanced by Anti-miR33 in Atherosclerosis.
• Rayner KJ. miR-155 in the Heart: The Right Time at the Right Place in the Right Cell. Circulation. 2015 Apr 7.
• Rayner KJ, Esau EC, Hussain FN, McDaniel AL, Marshall SM, van Gils JM, Ray TD, Sheedy FJ, Goedeke L, Liu X, Khatsenko OG, Kaimal V, Lees CJ, Fernandez-Hernando C, Fisher EA, Temel RE, Moore KJ. Inhibition of miR-33a and b in non-human primates raises plasma HDL cholesterol and reduces VLDL triglycerides. Nature. 2011; 478(7369):404-7.
• Rayner KJ, Sheedy FJ, Esau EC, Hussain FN, Temel RE, Parathath, van Gils JM, Rayner AJ, Chang AN, Suarez Y, Fernandez-Hernando C, Fisher EA, Moore KJ. Antagonism of miR-33 in Mice Promotes Reverse Cholesterol Transport and Regression of Atherosclerosis. Journal of Clinical Investigation. 2011; 21(7):2921-31.
• Rayner KJ*, Suarez Y*, Davalos A, Parathath S, Fitzgerald ML, Tamehiro N, Fisher EA, Moore KJ# and Fernandez-Hernando C#. miR-33 Contributes to the Regulation of Cholesterol Homeostasis. Science. 2010; 328(5985):1570-3. *,# Equal contribution.

Membres de l’équipe

• Michele Geoffrion
• Nancy Simon
• David Smyth
• Jonathan Salazar-Leon
• Chanele Polenz
• Cameron Stotts
• Abby Hudak
• Rama Sarakbi
• Serena Solari

Anciens membres

• Michelle Gandelman
• Adil Rasheed
• Claire Pedley
• Leah Susser
• Zier Zhou
• Yasmine Elmi
• Tala Salaheddin
• Emma McGinnis
• Taylor Dennison
• My-Anh Nguyen
• Anne-Claire Duchez
• Hailey Wyatt
• Benoit Laffont
• Mary-Lynn Cottee
• Denuja Karunakaran
• Zach Lister 

Chronic inflammation is a central player in a vast majority of age-related chronic diseases. Although inflammation is an attempt by the body to restore homeostasis, if it is sustained it can promote tissue destruction and dysfunction. Sterile inflammation, or that which is found in the absence of infection, underpins the progression of diseases of the heart, liver and brain, and contributes to co-morbidities such as obesity and autoimmune diseases. Research conducted in this laboratory focuses on the intersection of inflammation, metabolism, and chronic disease, particularly disease of the cardiovascular system, and how scientists can target this underlying inflammation to better diagnose and treat chronic disease. The goal of the Vascular Inflammation and Metabolism Laboratory is to identify the molecular underpinnings of metabolically-driven inflammatory diseases and identify specific pathways that can be targeted therapeutically and diagnostically to reduce tissue injury and disease. Previous work of this laboratory sought to understand which inflammatory pathways go awry in atherosclerotic plaques that render them prone to rupture. A vulnerable plaque leads to a vulnerable patient – one that is at high risk of having a heart attack. The research team’s work identified a key pro-inflammatory cell death pathway, termed necroptosis, that is uniquely active in advanced human plaques and correlates with risk of plaque rupture. In preclinical studies, blocking members of this pathway (RIPK1, RIPK3, MLKL) using small molecules, RNA-based drugs and/or genetic deletion leads to reduced disease. Importantly, the research team also used this pathway to develop a novel radiotracer for diagnostic imaging that can help identify advanced atherosclerotic plaques.

The Vascular Inflammation and Metabolism Laboratory team will take its discoveries to the next level by determining the unique pathways that cause inflammation during metabolic stress, how they are distinct from those that protect the host from pathogens, and which of these pathways are shared in the heart, the brain and other organs.

Theme 1: Inflammatory cell death and inflammation in atherosclerosis

Following the retention of lipoproteins in the vessel wall, the environment can induce the modification of LDL into oxidized and aggregated forms, which activate innate immune sensing pathways. During Dr. Katey Rayner’s postdoctoral studies, she and her team uncovered an essential role for the NLRP3 inflammasome, triggered by oxLDL binding to CD36, in inflammatory atherosclerosis. The research team then delineated the upstream pathways that activate necroptosis, a pro-inflammatory form of cell death that acts in concert with the inflammasome but releases DAMPs during cell membrane rupture. Importantly, Dr. Rayner’s laboratory was the first to show MLKL activation in advanced vulnerable human atherosclerosis. The research team also discovered that hyperlipidemia causes the reprogramming of splenic endothelial cells, causing them to alter hematopoiesis via MLKL – a protein previously believed to be only involved in necroptotic cell death, but is now understood to regulate endocytic trafficking. MLKL is required to repress splenic hematopoiesis and without it, there is an increase in monocytes that travel to plaque macrophages and accelerate atherosclerosis.

Theme 2: RIP kinases in metabolic inflammation, obesity & atherosclerosis

The family of RIP kinases, including RIPK1 and RIPK3, coordinate inflammatory and cell death signals in normal and pathophysiological processes. Dr. Rayner’s research team found that genetic variants in the human RIPK1 gene increase the expression of RIPK1 in adipose tissue, and this increases the risk of obesity. This is the first evidence of a genetic risk factor for obesity in an inflammatory gene, which has important implications for new anti-obesity therapies. RIPK1 expression is elevated in human atherosclerotic plaques, and in mouse models of either atherosclerosis or diet-induced obesity, and RIPK1 can be silenced to reduce inflammation and disease.

Theme 3: Non-coding RNA regulation of lipid metabolism, inflammation and atherosclerosis

In 2010, while completing her postdoctoral fellowship, Dr. Rayner was among the first to uncover a role for microRNAs, particularly miR-33, in the regulation of HDL cholesterol in mice and humans. These studies set the platform for intensive investigation into how miRNAs function to regulate macrophage and hepatic lipid metabolism and atherosclerosis and they formed the basis for therapeutic development of miR-33 inhibitors by Regulus Therapeutics in 2012. More recently, Dr. Rayner and her research team have expanded the understanding of extracellular miRNAs and how they control cholesterol handling and inflammation, and how they can be exploited therapeutically.

Theme 4: Macrophage inflammatory & resolution programs in the vessel wall

Atherosclerosis progression and regression are both defined by the balance of pro- and anti-inflammatory programs in and of the vessel wall.  Once inflammation is triggered, Dr. Rayner’s team has found that macrophages use their mitochondria as key signaling mediators of inflammatory signalling: pro-inflammatory macrophage mitochondria adopt hyperfused morphology, but mitochondrial fragmentation/fission is critical for macrophages to convert to a pro-resolving phenotype, involving lactate epigenetic signalling. These pathways build on previous findings that the atherosclerotic milieu contains main cues to attract inflammatory cells and then trap them within the plaque, ultimately promoting lesion development.

Opportunities

To enquire about available positions, please submit your CV with a cover letter detailing what you can bring to the team.

Contact:
@email