Robert Gros, Scientist, Molecular Medicine: Vascular and Brain Health Group; Associate Professor, Departments of Physiology & Pharmacology and Medicine
As a kid I always enjoyed playing with my chemistry set and my microscope, but being at the hospital and visiting my Oma when she suddenly died of cardiac arrest due to diabetic complications was one of those moments that really ignited the fire to pursue a career in medical research.
The focus of my laboratory is to investigate the cellular and molecular mechanisms involved in the regulation of vascular and cardiac function. In particular, we are interested in the role and regulation of G-protein-coupled receptor signaling pathways in both vascular smooth muscle cell,?endothelial cell and cardiomyocyte function under physiological and pathological conditions such as high blood pressure (hypertension),?diabetes or heart disease.?
The regulation of vascular and cardiac function is complex and involves many different signaling pathways, including the large family of G-protein-coupled receptors (GPCRs) and adenylyl cyclases.?? We and other have identified that impaired function in these signaling pathways is associated with hypertension and heart disease.? This impairment in GPCR-mediated function is in part due to increased expression/ function of G-protein-coupled receptor kinases. However, the cellular/molecular mechanism(s) involved in the regulation of altered GRK expression during the hypertensive state (or other pathological conditions) is unknown and is the focus of my laboratory’s research effort.??
Understanding the regulation of G-protein-coupled receptor kinases (GRKs) in cardiovascular disease.? ?
The function of G-protein-coupled receptors is altered in diseases such as high blood pressure and heart disease.? These diseases are associated with higher expression levels of GRKs, but why and how these levels are increased in unknown.??
Identification of novel cardiovascular G-protein-coupled receptor signaling pathways under physiological and patho-physiological conditions.
The rapid vascular actions of steroid hormones such as estrogen and aldosterone are in part mediated by a recently discovered G-protein-coupled receptor, GPR30.? The vascular actions of steroid hormones have been implicated in both hypertension and heart disease.? However, the role of GPR30 and its signaling pathways in cardiovascular disease in unknown.
Understanding the role of the neuronal and non-neuronal cholinergic systems in cardiovascular regulation.
Acetylcholine is the major chemical messenger regulating autonomic functions.? Cholinergic neurons regulate many bodily functions and organs, including the heart.? In addtion, the potential role of a non-neuronal cholinergic system present in cardiomyocytes themselves is also being investigated by our laboratory.? This research examining the role of these cholinergic systems has started to uncover novel mechanisms that regulate the activity of the heart and may have implications to develop novel treatments for heart failure.
Understanding the role of different adenylyl cyclase isoforms in cardiovascular regulation.
Adenylyl cyclase plays a critical role in the function and regulation of many different cell types, including blood vessel and heart cells.? We have recently identified that different adenylyl cyclase isoforms have distinct roles in regulating cellular function.? Additionally, we have recently identified a variant (polymorphism) of adenylyl cyclase isoform VI, which is associated with alterations in blood pressure and heart rate regulation in human subjects.? What role this variant plays in cardiovascular disease development or progression is unknown.
??Ph.D., Pharmacology, The University of Western Ontario, London, Ontario
??Toronto General Hospital, University of Toronto, Toronto, Ontario
??Robarts Research Institute, London, Ontario?
??New Investigator Award, Canadian Hypertension Society/Biovail
??The Dr. Maureen Andrew New Investigator Award, Heart and Stroke Foundation of Ontario
??New Investigator Award, Heart and Stroke Foundation of Canada
??The Evelyn McGloin Fellowship, Heart and Stroke Foundation of Ontario
??Fellowship Award , Heart and Stroke Foundation of Ontario
??The Edward Christie Stevens Fellowship in Medicine. Faculty of Medicine, University of Toronto
??Graduate Studentship Award, Canadian Hypertension Society/Pfizer/MRC
??Summer Student Research Scholarship in Medicine, PMAC/MRC?
??Tutunea-Fatan, E., Caetano, FA., Gros, R.*, and Ferguson, SSG.* GRK2 targeted knock-down results in spontaneous hypertension and altered vascular GPCR signaling. Journal of Biological Chemistry. 2015 Feb 20; 290(8):5155. *Co-Corresponding Authors.
??Hussain, Y., Ding, Q., Connelly, PW., Brunt, JH., Ban, MR., McIntyre, AD., Huff, MW., Gros, R., Hegele, RA., and Feldman, RD. G-protein estrogen receptor as a regulator of low-density lipoprotein cholesterol metabolism: cellular and population genetic studies. Arteriosclerosis Thrombosis and Vascular Biology. 2015 Jan; 35(1):213-221.
??Thompson, JA., Sarr, O., Piorkowska, K., Gros, R., Regnault, TRH. Low birth weight followed by postnatal over-nutrition in the guinea pig exposes a predominat player in the development of vascular dysfunction. Journal of Physiology. 2014 Dec 15; 592(Pt 24):5429-5443.
??Ding, Q., Hussain, Y., Chorazyczewski, J., Gros, R., Feldman, RD. GPER-independent effects of estrogen in rat aortic vascular endothelial cells. Journal of Molecular and Cellular Endocrinology. 2015 Jan 5: 399:60-68.
??Feldman, RD., Gros, R., Ding, QM., Hussain, Y., Ban, MR., McIntyre, AD., and Hegele, RA. A common hypofunctional genetic variant of GPER is associated with increased blood pressure in women. British Journal of Clinical Pharmacology. 2014 Dec; 78(6):1441-1452.
??Bojic, LA., Telford, DE., Fullerton, MD., Ford, RJ., Sutherland, BG., Edwards, JY., Sawyez, CG., Gros, R., Kemp, BE., Steinberg, GR., and Huff, MW. PPARδ activation attenuates hepatic steatosis in Ldlr-/-mice by enhanced fat oxidation, reduced lipogenesis and improved insulin sensitivity. Journal of Lipid Research. 2014 May 26; 55(7):1254-1266.
??Albers, S., Inthathirath, F., Gill, SK., Winick-Ng, W., Jaworski, E., Wong, DY., Gros, R., and Rylett RJ. Nuclear 82-kDa choline acetyltransferase decreases amyloidogenic APP metabolism in neurons from APP/PS1 transgenic mice. Neurobiology of Disease, 2014 Sep; 69:32-42
??Chidiac, P., Sobiesiak, AJ., Lee, KN., Gros, R., and Nguyen, C. The elF2B-interacting domain of RGS2 protects against GPCR agonist-induced hypertrophy in neonatal rat cardiomyocytes.?Cellular Signalling. Jun; 26(6):1226-1234.
??Roy, A., Fields, CW., Rocha-Resende, C., Resende, RR., Guatimosim, S., Prado, VF., Gros, R.* and Prado, MAM.* Cardiomyocyte-secreted acetylcholine is required for maintenance of homeostasis in the heart. FASEB Journal. 2013 Dec; 27(12):5072-5082. *Co-Senior and Co-Corresponding Authors - contributed equally.
??Vafaie, F., Yin, H., O'Neil, C., Nong, Z., Watson, A., Arpino, JM., Chu, MW., Holdsworth, D., Gros, R., Pickering, JG. Collagenase-resistant collagen promotes mouse aging and vascular cell senescence. Aging Cell. 2014 Feb; 13(1):121-130.
??Kolisnyk, B., Guzman, MS., Raulic, S., Fan, J., Magalh?es, AC., Feng, G., Gros, R., Prado, VF., Prado, MA. ChAT-ChR2-EYFP mice have enhanced motor endurance but show deficits in attention and several additional cognitive domains.? The Journal of Neuroscience. 2013 Jun 19; 33(25):10427-10438.
??Beraldo, FH., Soares, IN., Goncalves, DF., Fan, J., Thomas, AA., Santos, TG., Mohammad, AH., Roffé, M., Calder, MD., Nikolova, S., Hajj, GN., Guimaraes, AL., Massensini, AR., Welch, I., Betts, DH., Gros, R., Drangova, M., Watson, AJ., Bartha, R., Prado, VF., Martins, VR., Prado, MA. Stress-inducible phosphoprotein 1 has unique cochaperone activity during development and regulates cellular response to ischemia via the prion protein. FASEB Journal 2013 Sep; 27(9):3594-3607.
??Gros, R., Ding, QM., Liu, B., Chorazyczewski, J., Feldman, RD. Aldosterone mediates its rapid effects in vascular endothelial cells through GPER/GPR30 activation. American Journal of Physiology. Cell Physiology. 2013 Mar; 304(6):C532-C540
??Assini, JM., Mulvihill, EE., Sutherland, BG., Telford, DE., Sawyez, CG., Felder, SL., Edwards, JY., Gros, R., Huff, MW. Naringenin prevents the cholesterol-induced systemic inflammation, metabolic dysregulation, and atherosclerosis in Ldlr-/-mice. Journal of Lipid Research. 2013 Mar; 54(3):711-724.
??Guzman, MS., De Jaeger, X., Caron, MG., Prado, MAM., Gros, R*., and Prado, VF*. Mice with selective elimination of striatal acetylcholine release are lean, show altered entergy homeostasis and changed sleep/wake cycle. Journal of neurochemistry. 2013 Mar; 124(5):658-669. *Co-Senior and Co-Corresponding Authors.
??Roy, A., Lara, A., Guimar?es, D., Pires, R., Gomes, ER., Carter, DE., Gomez, MV., Guatimosim, S., Prado, MAM, and Gros, R.? An alalysis of the myocardial transcriptome in a mouse model of cardiac dysfunction with decreased cholinergic neurotransmission.? PLoS One. 2012;7(6):e39997.
??Rocha-Resendea, C., Roy, A., Resende, R., Lara, A., Gomes, ER., Prado, VF., Gros, R., Guatimosim, C., Prado, MAM., and Guatimosim, S.??Non-neuronal cholinergic machinery present in cardiomyocytes offsets hypertrophic signals.? Journal of Molecular and Cellular Cardiology.? 2012 Aug;53(2):206-216.
??Nong, Z., O'Neil, C., Lei, M., Gros, R., Watson, A., Rizkalla, A., Mequanint, K., Li, S., Frontini, MJ., Feng, Q., and Pickering JG.?? Type I collagen cleavage is essential for effective fibrotic repair following myocardial infarction.? American Journal of Phathology.? 2011 Nov;179(5):2189-2198.
??Thompson, JA., Gros, R., Richardson, BS., Piorkowska, K., and Regnault, TRH.? Central stiffening in adulthood linked to aberrant aortic remodeling under suboptimal intrauterine conditions.??American Journal of Physiology, Regulatory, Integrative and Comparative Physiology. 2011 Dec;301(6):R1731-1737.
??Gros, R., Ding, QM., Sklar, LA., Prossnitz, EE., Arterburn, JB., Chorazyczewski, J., and Feldman, RD.? GPR30 expression in required for the mineralocorticoid receptor-independent rapid vascular effects of aldosterone.? Hypertension.? 2011 Mar;57(3):442-451.
??Frontini, M., Nong, Z., Gros, R., Drangova, M., O'Neil, C., Rhaman, M., Akawi, O., Yin, H., Ellis, CJ., and Pickering JG.? Fibroblast growth factor 9 delivery during angionenesis produces durable, vasoresponsive microvessels wrapped by smooth muscule cells.? Nature Biotechnology.? 2011 May;29(5):421-427.
??Gros, R., Ding QM., Davis, M. Shaikh, R., Liu, B., Chorazyczewski, J., Pickering, JG, and Feldman, RD. Delineating the receptor mechanisms underlying the rapid vascular contractile effects of aldosterone and estradiol.? Canadian Journal of Physiology and Pharmacology. 2011 Sep;89(9):655-663.
? Lara, A#, Damasceno, DD#, Pires, R#, Gros, R#, Gomes, ER., Gavioli, M., Lima, RF., Guimar?es, D., Lima, P., Bueno Jr CR., Vasconcelos, A., Roman-Campos, D., Menezes, CA., Sirvente, RA., Salemi, VM., Mady, C., Caron, MG., Ferreira, AJ., Brum, PC., Resende, RR., Cruz, JS., Gomez, MV., Prado, VF., de Almeida, AP., Prado, MAM., Guatimosim, S.? Dysautonomia due to reduced cholinergic neurotransmission causes?cardiac remodeling and heart failure.? Molecular and Cellular Biology. 2010 Apr;30(7):1746-1756.? #authors contributed equally to manuscript.
? Hodges, GJ#, Gros, R#, Hegele, RA., Van Uum, S., Shoemaker, JK., Feldman, RD.? Increased blood pressure and hyperdynamic cardiovascular responses in carriers of a common hyperfunction variant of adenylyl cyclase 6.? Journal of Pharmacology and Experimental Therapeutics.? 2010 Nov;335(2):451-457.? #authors contributed equally to manuscript.
? Godin, CM., Ferreira, LT., Dale, LB., Gros, R., Cregan, SP., Ferguson, SSG.? The small GTPase Ral couples the angioitensin II type I receptor to the activation of phospholipase C-δ1.? Molecular Pharmacology. 2010 Mar;77(3):388-395.
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