Thomas J Gardella, Ph.D.
Endocrine Division, Mass General Research Institute
Associate Professor of Medicine
Harvard Medical School
Endocrine Division, Massachusetts General Hospital
|PhD UMASS School of Medicine 1988|
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.