The focus of my research is to understand the mechanisms that regulate the development and progression of heart failure. In particular, my research investigates the immunomodulatory role of adrenergic receptors and following cardiac injury and as a potential therapeutic target for the treatment of heart disease. β-adrenergic receptors (βAR) are critical regulators of cardiac function both in the healthy and diseased heart. Cardiac βAR are differentially expressed with the β1AR subtype being predominantly localized to cardiomyocytes where they are known to regulate contractility. β2AR are predominate on other cells types including fibroblasts and immune cells. During heart failure, βAR signaling becomes altered and subtype expression ratios change, leading to detrimental hypertrophy, increased cardiomyocyte apoptosis, fibrosis and cardiac dysfunction. As a result of this dysregulation in βAR signaling, they are a common therapeutic target for the treatment of heart diseases including myocardial infarction (MI) and heart failure.
Following MI, there is an intense inflammatory response that is critical to for clearing the area of dying cardiomyocytes and extracellular matrix debris and activating remodeling pathways. It has been known for over 100 years that the sympathetic nervous system can influence immune responses in part through its activation of βAR. βAR are expressed on virtually all cells of the immune system where they impact cell function in a cell type, activation state and disease dependent manner. β2AR are the most highly and widely expressed βAR subtype in the immune system where they are known to influence a number of different functions including hematopoiesis, lymphopoiesis, thymopoiesis, lymphocyte homing, immune cell maturation and immune cell function. Regulation of immune functions by β2AR is thought to contribute to a number of different diseases including autoimmune diseases and wound healing. However, the manner in which β2AR regulate immune responses is often disease dependent and how β2AR regulation of immune responses influences the pathogenesis and progression of heart failure is completely unknown. We have identified an important role for β2AR in suppressing early immune responses, which leads to impairments in the hearts ability to remodel following ischemic injury. Mice that lack β2AR in their immune system have decrease leukocyte infiltration following MI as a result of decreased migratory ability through alterations in the chemokine receptor CCR2. There are also impairments in egress of immune cells from the spleen. Ongoing studies are investigating the role of β2AR in regulating specific immune cell populations that impact healing following MI, identifying novel mechanisms through which β2AR are influencing the immune response, the impact of β-blockers on inflammatory responses and novel therapeutic strategies targeting β2AR in the immune system to improve outcome after MI.
Publications:
- Grisanti LA, Shumacher SM, Tilley DG and Koch WT (2017) Designer Approaches to GPCR Modulation. JACC Basic Transl Sci. In Press.
- Guo S, Carter RL, Grisanti LA, Koch WJ and Tilley DG (2017) Impact of Paroxetine on Proximal β-Adrenergic Receptor Signaling. Cell Signal. 38:127-33.
- Verma SK, Garikipati VN, Krishnamurthy P, Schumacher-Bass SM, Grisanti LA, Cimini M, Cheng Z, Khan M, Yu Y, Benedict C, Truongcao MM, Rabinowitz JE, Goukassian DA, Tilley DG, Koch WJ and Kishore R (2017) Interleukin 10 Inhibits Bone Marrow Fibroblast Progenitor Cell-Mediated Cardiac Fibrosis in Pressure Overload Myocardium. Circulation. 136:940-953.
- Grisanti LA, Guo S and Tilley DG. G Protein-Coupled Receptor-Mediated Epidermal Growth Factor Receptor Transactivation in the Cardiovascular System. 2017; J Cardiovasc Pharmacol; J Cardiovasc Pharmacol. 70:3-9.
- Grisanti LA, Traynham CJ, Gao E, Koch WJ and Tilley DG (2016) β2-Adrenergic Receptor-Dependent Chemokine Receptor 2 Expression Regulates Leukocyte Recruitment to the Heart Following Acute Injury. Proc Natl Acad Sci USA; 113:15126-15131.
- Wasilewski WA, Grisanti LA, Song J, Carter RL, Repas AA, Myers VD, Gao E, Koch WJ, Cheung JY, Feldman AM and Tilley DG (2016) Vasopression Type 1A Receptor Deletion Enhances Cardiac Contractility and β-Adrenergic Receptor Sensitivity. Clinical Science; In Press.
- Woodall BP, Woodall MC, Luongo TS, Grisanti LA, Tilley DG, Elrod JW and Koch WJ (2016) Skeletal Muscle Specific GRK2 Ablation Alters Isolated Skeletal Muscle Mechanics and Enhances Clenbuterol-Stimulated Hypertrophy. J Biol Chem; 291:21913-24.
- Grisanti LA, Gumpert AM, Traynham CJ, Gorsky JM, Repas AA, Gao E, Carter RL, Yu D, Calvert JW, Pun Garcia A, Ibanez B, Rabinowitz JE, Koch WJ and Tilley DG (2016) Hematopoietic Expression of β2-Adrenergic Receptors is Critical for Survival Following Myocardial Infarction. Circulation; 134:153-67.
- Grisanti LA, Repas AA, Carter RL, Talarico JA, Gold JL, Koch WJ and Tilley DG. 2014. Temporal Regulation of Cardiac Cytokine Expression in Response to Chronic β-Adrenergic Receptor Stimulation. Am J Physiol Heart; 38:316-30.
- Hullmann JE, Grisanti LA, Makarewich CA, Gao E, Gold JI, Chuprun JK, Tilley DG, Houser SR and Koch WJ (2014) GRK5-Mediated Exacerbation of Pathological Cardiac Hypertrophy Involves Facilitation of Nuclear NFAT Activity; Circ Res. 115:976-85.
- Tilley DG, Zhu W, Myers VD, Barr LA, Gao E, Li X, Song J, Carter RL, Makarewich CA, Troupes CD, Grisanti LA, Coleman RC, Koch WJ, Houser SR, Cheung JY and Feldman AM (2014) β-Adrenergic Receptor-Mediated Cardiac Contractility is Inhibited via Vasopressin Type 1A-Receptor-Dependent Signaling. Circulation; 130:1800-11.
- Talarico JA, Carter RL, Grisanti LA, Yu JE, Repas AA and Tilley DG (2014) β-Adrenergic Receptor-Dependent Alterations in Murine Cardiac Transcript Expression are Differentially Regulated by Gefitinib In Vivo. PLoS One; 9(6):e99195.
- Grisanti LA, Talarico JA, Carter RL, Yu JE, Repas AA, Radcliffe SW, Tang H, Makarewich CA, Houser SR and Tilley DG (2014) β-Adrenergic Receptor-Mediated Transactivation of Epidermal Growth Factor Receptor Decreases Cardiomyocyte Apoptosis Through Differential Subcellular Activation of ERK1/2 and Akt; J Mol Cell Cardiol. 72:39-51.
- Carter RL, Grisanti LA, Yu JE, Repas AA, Woodall M, Ibetti J, Koch WJ, Jacobson MA and Tilley DG (2014) Dynamic Mass Redistribution Analysis of Endogenous β-Adrenergic Receptor Signaling in Neonatal Rat Cardiac Fibroblasts; Pharma Res Per. 2(1):e00024.
- Yu J, Deliu E, Zhang XQ, Hoffman NE, Carter RL, Grisanti LA, Brailoiu GC, Madesh M, Cheung JY, Force T, Abood ME, Koch WJ, Tilley DG and Brailoiu E (2013) Differential Activation of cultured Neonatal Cardiomyocytes by Plasmalemmal Versus Intracellular G Protein-Coupled Receptor 55. J Biol Chem; 288(1):22481-92.
- Grisanti LA, Kurada L, Cilz NI, Porter JE and Lei S (2012) Phospholipase C not Protein Kinase C is Required for the Activation of TRPC5 Channels by Cholecystokinin. Eur J Pharmacol; 689(1-3):17-24.
- Grisanti LA, Perez DM and Porter JE. Modulation of Immune Cell Function by α1-Adrenergic Receptor Activation. Curr Top Membr 2011; 67:113-38.
- Grisanti LA, Woster AP, Dahlman J, Sauter ER, Combs CK and Porter JE (2010) α1-Adrenergic Receptors Positively Regulate Toll-like Receptor Cytokine Production from Human Monocytes and Macrophages; J Pharmacol Exp Therap. 338(2):648-57.
- Grisanti LA, Evanson J, Marchus E, Jorissen H, Woster AP, DeKrey W, Sauter ER, Combs CK and Porter JE (2010) Pro-Inflammatory Responses in Human Monocytes are β1-Adrenergic Receptor Subtype Dependent; Mol Immunol. 47(6):1244-54.
- Deng P, Rojanathammanee L, Xiao Z, Yang C, Grisanti L, Watt J, Geiger JD, Liu R, Porter JE and Lei S (2009) GABAB Receptor Activation Inhibits Neuronal Excitability and Spatial Learning in the Entorhinal Cortex by Activating TREK-2 K+ Channels; Neuron. 63(2):230-43.
- Xiao Z, Deng P, Rojanathammanee L, Yang C, Grisanti L, Permpoonputtana K, Weinshenker D, Doze VA, Porter JE and Lei S (2009) Noradrenergic Depression of Neuronal Excitability in the Entorhinal Cortex via Activation of TREK-2 K+ Channels; J Biol Chem. 284(16):10980-91.
- Rojanathammanee L, Harmon EB, Grisanti LA, Govitrapong P, Ebadi M, Grove BD, Miyagi M and Porter JE (2009) HSP27 Confers Cytoprotective Effects Through a β-Adrenergic Receptor Agonist-Initiated Complex with β-Arrestin. Mol Pharm; 75(4):855-65.
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