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Research in the Gardella group is focused on exploring the molecular mechanisms by which the parathyroid hormone receptor, the PTHR, binds extracellular ligands and relays signaling information to the cytoplasmic domain of target cells.
The PTHR is a seven-transmembrane domain-containing, G protein-coupled receptor (GPCR). It is expressed on the surface of bone and kidney cells and plays a critical role in bone growth and development, as well as in the maintenance of blood calcium ion homeostasis.
It is activated by two endogenous peptide ligands, parathyroid hormone (PTH) and PTH-related protein (PTH-rP). Current data suggest that the peptide ligands bind to the PTHR through a mechanism that involves multiple points of contact between the ligand and molecular determinants displayed along the contours of the receptor’s extracellular surface.
This binding then induces conformational movements of the seven membrane-spanning a-helices, which, in turn, enable coupling to a cytoplasmic G protein, and hence activation of a specific intracellular signaling cascade, such as cAMP/PKA or IP3/PKC.
By using a combination of molecular, pharmacological and microscopic approaches to explore these processes, we hope to uncover new basic mechanisms of peptide-hormone-GPCR action. Moreover, by designing new PTH and PTHrP ligand analogs that bind via distinct mechanisms and selectively activate altered signaling responses, we hope to reveal clues that may help in the development of new therapies for diseases of bone and mineral ion metabolism, such as osteoporosis, hypoparathyroidism and Jansen’s chondrodysplasia.
Thomas Gardella, PhDAssistant Professor in Medicine and Biochemistry, Harvard Medical SchoolMassachusetts General Hospital Endocrine Unit
Molecular mechanisms of PTH ligand binding to the PTH receptor and receptor signaling. Exploration of molecular determinants of receptor binding affinity and activation potency. Development of PTH peptide ligands with optimized affinity and potency, and mapping sites of contact in the PTH receptor. Microscopic tracking of fluorescently labeled ligands and tagged receptors through intracellular pathways of endocytosis; further assessment of the new mechanisms of endosomal signaling revealed by this lab using PTH ligands receptor.
Testing of optimized PTH analogs for efficacy in animal models of osteoporosis.
Development of long-acting PTH agonists for potential treatment of hypoparathyroidism. Pegylation of PTH ligands to prolong pharmacokinetic half-time in the blood and pharmacodynamic effects on blood calcium. Modification of peptide side chain and/or backbone structure to achieve pseudo-irreversible binding to the PTH receptor and hence prolonged signaling and calcemic effects in vivo, independent of pharmacokinetics. Assessment of such long-acting PTH analogs in animal models of hypoparathyroidism.
Development of new antagonist and inverse agonist analogs of PTH ligands and assessment of such antagonist/inverse agonists in mouse models of hyperparathyroidism and hypercalcemia of malignancy for the capacity to lower blood calcium levels to normal. Further assess inverse agonists in mouse models of Jansen’s metaphyseal chondrodysplasia for the capacity to correct the skeletal deformities that occur in this rare disease of bone development.
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