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Research Description:
G protein-coupled receptors (GPCRs) represent a major class of membrane-bound proteins that mediate a wide variety of biological functions, including sensitivity to light and odorants, endocrine and cardiovascular control, and neurotransmission. Because of their central role in many physiological processes, GPCRs represent one of the major targets for pharmacological intervention in a large number of pathologies.
The goal of our research program is the elucidation of the molecular mechanisms that determine activation, regulation and trafficking of GPCRs and their relevance to the (patho)physiology of peptide hormones.
These studies provide the opportunity to address key issues regarding the mode and specificity of actions of G protein-coupled receptors. Most importantly, these studies may provide the basis for the identification of novel therapeutic targets for the treatment of osteoporosis, diabetes and vasculopathies.
The general scientific theme in the laboratory is to define the role of accessory proteins (such as arrestins, caveolin, EBP50/NHERF1) in determining G protein-coupled receptor function. Our efforts focus on two specific areas:
1.) The signaling, trafficking and regulation of the parathyroid hormone type 1 and type 2 receptors (PTH1R and PTH2R) and their function in vascular smooth muscle cells, with particular emphasis on their role in mitogenesis. The cardiovascular tissue, and in particular vascular smooth muscle cells (VSMC), expresses and be exposed to the whole spectrum of parathyroid hormone ligand-receptor systems. VSMC express both the type 1 and type 2 parathyroid hormone receptors (PTH1R and PTH2R, respectively). Also, in addition to being exposed to circulating parathyroid hormone (PTH), they produce parathyroid hormone-related protein (PTHrP) and tuberoinfundibular peptide of 39 residues (TIP39). This complexity reflects the varied and distinct actions of these ligands and receptors in both pathophysiology and pharmacology of the cardiovascular system. The central hypothesis of this project is that signaling and regulation of the PTH receptors in VSMC, and consequently the tissue-specific responses, are determined by the expression and function of adaptor proteins.
2.) Cellular regulation of the glucagon-like peptide 1 (GLP-1R) receptor and its role in regulating beta cell function, proliferation and survival.One of the most promising therapeutic targets for the treatment of type 2 diabetes is the glucagon-like peptide 1 receptor (GLP-1R). The well documented ability of GLP-1R agonists, either GLP-1 itself or exendin-4, to stimulate glucose-dependent insulin secretion and increase beta cell proliferation and survival led to the approval of exendin-4 for the treatment of type 2 diabetes. Our studies show that the GLP-1R interacts with caveolin1 and this is necessary for the trafficking of the GLP-1R to the cell membrane and directs its localization to lipid rafts. The central hypothesis of this project is that the interaction between GLP-1R and caveolin1 and its localization in lipid rafts is a fundamental mechanism controlling both the insulinotropic and the proliferative actions of GLP-1 and exendin-4.
Education:
Laurea (Chemistry), University of Padova, Italy, 1992. Postdoctoral Fellow, Biopolymer Research Center, University of Padova, Italy, 1992-1994. Postdoctoral Fellow, Beth Israel Deaconess Medical Center, Harvard Medical School, 1994-1996.
Important Publications:
- Song GJ, N Fiaschi-Taesch and A Bisello. Endogenous parathyroid hormone-related protein regulates the expression of PTH type 1 receptor and proliferation of vascular smooth muscle cells. Mol Endocrinol 23:1681-1690, 2009
- Fiaschi-Taesch N, BM Sicari, K Ubriani, T Bigatel, KK Takane, I Cozar-Castellano, A Bisello, B Law and AF Stewart. Cellular mechanism through which parathyroid hormone-related protein induces proliferation in arterial smooth muscle cells: definition of an arterial smooth muscle PTHrP/p27kip1 pathway. Circ Res 99:933-942, 2006
- Syme CA, L Zhang and A Bisello A. Caveolin-1 regulates cellular trafficking and function of the glucagon-like peptide 1 receptor. Molecular Endocrinology 20:3400-3411, 2006
- Syme CA, PA Friedman and A Bisello. Parathyroid hormone receptor trafficking contributes to the activation of extracellular signal-regulated kinases but is not required for regulation of cAMP signaling. J Biol Chem 280:11281-11288, 2005
- Bisello A, D Manen, DD Pierroz, TB Usdin, R Rizzoli and SLFerrari. Agonist-specific regulation of parathyroid hormone (PTH) receptor type 2 activity: structural and functional analysis of PTH- and tuberoinfundibular peptide (TIP) 39-stimulated desensitization and internalization. Mol Endocrinol 18:1486-1498, 2004
- Bisello A, M Chorev, M Rosenblatt, L Monticelli, DF Mierke and SL Ferrari. Selective ligand-induced stabilization of active and desensitized parathyroid hormone type 1 receptor conformations. J Biol Chem 277:38524-38530, 2002
- Ferrari SL and A Bisello. Cellular distribution of constitutively active mutant parathyroid hormone/parathyroid hormone-related protein receptors and regulation of 3’, 5’-cyclic AMP signaling by β-arrestin2. Mol Endocrinol 15:149-163, 2001
- Ferrari SL, Behar V, Chorev M, Rosenblatt M and Bisello A. Endocytosis of ligand--human parathyroid hormone receptor 1 complexes is protein kinase C-dependent and involves β-arrestin2: Real-time monitoring by fluorescence microscopy. J Biol Chem 1999;274:29968-29975., 1999
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