Appropriate regulation of osteoclast-mediated bone resorption is essential for maintenance of healthy bone. Understanding the molecular regulation of osteoclasts may lead to new therapeutic approaches to common serious bone diseases like osteoporosis. Osteoclasts resorb bone by generating an acidic compartment on the bone surface. A key component of the osteoclast acid transport mechanism is a chloride channel which is expressed in the osteoclast-ruffled border. The applicant's long-term goals have been to identify the molecular basis of the ruffled border chloride channel and to understand how this channel may regulate acid transport and bone resorption.
The Specific Aims of the present proposal are to: (1) complete molecular cloning of the sequences encoding the ruffled membrane chloride channel; (2) biochemically characterize the channel complex; (3) explore the relationship between the chloride channel and the non-receptor tyrosine kinases, src, and; (4) define the mechanism by which the presence of bone regulates expression of the chloride channel.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
1R01AR044838-01
Application #
2448844
Study Section
Orthopedics and Musculoskeletal Study Section (ORTH)
Project Start
1998-04-01
Project End
2002-03-31
Budget Start
1998-04-01
Budget End
1999-03-31
Support Year
1
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Barnes-Jewish Hospital
Department
Type
DUNS #
City
Saint Louis
State
MO
Country
United States
Zip Code
63110
Tulk, Barry M; Kapadia, Shefalee; Edwards, John C (2002) CLIC1 inserts from the aqueous phase into phospholipid membranes, where it functions as an anion channel. Am J Physiol Cell Physiol 282:C1103-12
Shanks, Ryan A; Larocca, M Cecilia; Berryman, Mark et al. (2002) AKAP350 at the Golgi apparatus. II. Association of AKAP350 with a novel chloride intracellular channel (CLIC) family member. J Biol Chem 277:40973-80
Tulk, B M; Schlesinger, P H; Kapadia, S A et al. (2000) CLIC-1 functions as a chloride channel when expressed and purified from bacteria. J Biol Chem 275:26986-93
Edwards, J C; Kapadia, S (2000) Regulation of the bovine kidney microsomal chloride channel p64 by p59fyn, a Src family tyrosine kinase. J Biol Chem 275:31826-32