Sarcoidosis and lymphoma, both AIDS and non-AIDS-associated, are relatively common human immunoproliferative diseases that may be complicated by a derangement of endogenous vitamin D metabolism. The development of active vitamin D metabolite- mediated hypercalciuria and/or hypercalcemia in patients with these diseases is a morbid (and sometimes life-threatening) event that requires immediate interventive therapy. The cellular source and structural identity of the offending vitamin D metabolite in sarcoidosis are known to be the macrophage and 1,25- dihydroxyvitamin D (1,25(OH)2-D), respectively; in lymphoma neither the source nor the identity of the hypercalcemia-causing metabolite is known.
The specific aims of the current application are to: 1) comprehend the mechanism(s) by which 1,25-(OH)2-D synthesis is regulated in sarcoid macrophages by the use of inhibitory agents that can be used safely in the treatment of patients with the disease; 2) define the source, identity, and regulation of the active vitamin D metabolite synthesized in some patients with lymphoma; and 3) explore the role of retroviruses, including the AIDS virus (HIV), in modulating the expression of active vitamin D metabolite synthesis by human immune cells. To investigate the deregulation of vitamin D metabolism in sarcoidosis and lymphoma we will employ primary cultures of pulmonary alveolar macrophages and lymphoma cell lines, respectively, established from hypercalcemic/hypercalciuric patients with sarcoidosis and lymphoma. Vitamin D metabolism in vitro will be performed by HPLC analysis of lipid extracts of cells incubated with (3H)25-hydroxyvitamin D3. Infection of established cell lines of immune cell origin with human retrovirus will be employed to probe the molecular mechanism underlying the putative 1-hydroxylase in inflammatory cells. The long term goals of this work are to: 1) isolate and characterize the putative 1-hydroxylase in human immune cells; 2) clone the cDNA(S) and gene(s) which encode the hydroxylase and/or proteins that are transactivators of the enzyme; and 3) more clearly define a potential contributory role for endogenously-synthesized active vitamin D metabolites in acquired immune deficiency states including sarcoidosis and AIDS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK033139-04
Application #
3231493
Study Section
General Medicine B Study Section (GMB)
Project Start
1985-07-01
Project End
1989-06-30
Budget Start
1988-07-01
Budget End
1989-06-30
Support Year
4
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Southern California
Department
Type
Schools of Medicine
DUNS #
041544081
City
Los Angeles
State
CA
Country
United States
Zip Code
90033