Oganesian Laboratory

 

PI: Anush Oganesian, PhD

Research Description

We study molecular mechanisms underlying signaling of adrenergic receptors (ARs) in health and disease, focusing primarily on the regulation and function of one ofthe stress hormone binding receptors, α1aAR. Three α1AR subtypes are expressed in the human heart and vasculature (α1a, α1b, α1d), mediating actions of the sympathetic nervous system through binding of endogenous catecholamines epinephrine and norepinephrine. Canonical signaling of α1ARs involves coupling to Gq/11, activation of PLC-β, and cleavage of PIP2 to diacylglycerol and inositol triphosphate (IP3). Receptor signaling is terminated by phosphorylation and subsequent binding of barrestins, which classically desensitizes the receptor and alters trafficking. New emerging data from our and other laboratories indicate that barrestins also initiate signaling in a G protein-independent manner, which is becoming an increasingly appreciated route for GPCR signaling.Despite the evidence that α1aAR stimulation is involved in myocardial hypertrophy and cardiac remodeling and the discovery of naturally occurring human α1aAR genetic variants in health and disease, the functional role of the α1aAR and its genetic variants remains elusive. Our studies are focused on examining molecular signaling of genetic variants of α1aAR in comparison with the wild type receptor. We recently discovered that G247R SNP in the 3rd intracellular loop functionally important for Gq-coupling (247R, identified in a severely hypertensive patient), constitutively activates the Gq-independent, barrestin1/MMP7/EGFR-transactivation pathway in fibroblasts (PNAS, 2011). Our recent studies in cardiomyoblasts andSMC revealed a unique 247R-triggered constitutive MMP/EGFR/ERK transactivation pathway, which is novel for GPCRs and may represent a new mechanism for some forms ofsympathetically-mediated hypertension (resistant hypertension) triggered by naturally occurring human genetic variants. It is particularly remarkable that the naturally occurring human genetic variant is the cause of these events. . Our findings also reveal that some α1aAR genetic variants trigger hyperproliferation and/or hypertrophy in smooth muscle cells and cardiomyoblasts, and that 247R induces cardiomyoblast transition to fibroblast-like cells, unraveling the potential involvement of α1aARs in the development of hypertension, myocardial fibrosis and heart failure.

Our current research is focused on cell reprogramming and generation of human stem cell models for cardiovascular disorders. We employ TALEN gene editing technology and cell reprogramming to generate human cardiomyocytes and smooth muscle cells expressing various naturally occurring genetic variants of α1aARs in the same genetic background as their normal counterpart. These human cardiovascular cells differentiated from the pluripotent stem cells are uniquely suited for our studies to:

  • Determine the functional properties of human endogenous α1aAR and its naturally occurring genetic variants expressed from their native promoter
  • Elucidate signal transduction pathways in the presence or absence of agonist stimulation triggered by α1aAR and its genetic variants identified in patient populations enriched with cardiovascular disorders such us hypertension and cardiomyopathy
  • Examine the cross talk and transactivation of different signaling pathways involving α1aAR and various tyrosine kinase receptors such as EGFR, PDGF and FGF
  • Determine the role of extracellular matrix proteins such as specific MMPs (matrix metalloproteinases) and ADAMs (a disintegrin and metalloproteinase) in the mechanistic signaling pathways activated by α1aARs and its genetic variants in health and various pathological conditions
  • Identify novel interacting partners of α1aAR and its genetic variants using various novel proteomics approaches.

Our studies are aiming to understand the functional role of endogenous α1aAR and its naturally occurring genetic variants in the development of human cardiovascular diseases, identification of new molecular targets in human cardiovascular cells and specific inhibitors as potentially novel therapeutic agents capable of restoring the normal phenotype.

Lab Members

  • Irina Gradinaru - Research Scientist
  • Ekaterina Babaeva - Research Scientist