Abstract

The PTH1R binding to scaffolding proteins is key to the actions of parathyroid hormone (PTH) and PTH-related peptide (PTHrP) in a cell- and membrane-specific manner. A receptor for PTH and PTHrP (PTH1R) belongs to G-protein coupling receptors (GPCR). PTH functions primarily to maintain calcium homeostasis through direct action on bone and kidney. PTHrP is a paracrine regulator of cellular growth and differentiation, and its ectopic expression in tumor cells is associated with bone metastasis and hypercalcemia in malignancy. Thus, to study signaling and physiological function of PTH1R via PTH and PTHrP is essential for understanding of mechanisms of diseases and developing novel therapy. The primary research goal is to investigate the role of calpain small subunits (the 28-kDa subunit), a novel interactor, binding to the parathyroid hormone 1 receptor (PTH1R) on PTH and/or PTHrP-mediated signaling and actions.
Specific Aim 1 defines calpain-mediated cleavage of the PTH1R and its role on PTH-mediated intracellular events.
Specific Aim 2 examines the role of calpain as a modulator of PTH-elicited downstream processes.
Specific Aim 3 characterizes the phenotype of mice with osteoblast-specific deletion of Capn4 in vivo and of Capn4-null osteoblsts isolated from these mice.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK072102-02
Application #
7097253
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Malozowski, Saul N
Project Start
2005-08-01
Project End
2010-05-31
Budget Start
2006-06-01
Budget End
2007-05-31
Support Year
2
Fiscal Year
2006
Total Cost
$313,679
Indirect Cost

  Institution

Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199

  Publications

Shimada, Masako (2013) Overview of calpain-mediated regulation of bone and fat mass in osteoblasts. Cell Biochem Biophys 66:23-8
Kashiwagi, Aki; Fein, Mikaela J; Shimada, Masako (2011) A high fat diet-induced impaired glucose metabolism in mice with targeted deletion of calpain in osteoblasts. Biochem Biophys Res Commun 409:235-40
Kashiwagi, Aki; Fein, Mikaela J; Shimada, Masako (2011) Calpain modulates cyclin-dependent kinase inhibitor 1B (p27(Kip1)) in cells of the osteoblast lineage. Calcif Tissue Int 89:36-42
Kashiwagi, Aki; Schipani, Ernestina; Fein, Mikaela J et al. (2010) Targeted deletion of Capn4 in cells of the chondrocyte lineage impairs chondrocyte proliferation and differentiation. Mol Cell Biol 30:2799-810
Shimada, Masako; Greer, Peter A; McMahon, Andrew P et al. (2008) In vivo targeted deletion of calpain small subunit, Capn4, in cells of the osteoblast lineage impairs cell proliferation, differentiation, and bone formation. J Biol Chem 283:21002-10