The general objectives of this research proposal are to define using, appropriate biochemical, cell biological and molecular biological techniques, the details of the participation of the vitamin D endocrine system in the differentiation and functioning of the human and murine hematopoietic system as well as the participation of the hematopoietic system in the vitamin D endocrine system. The program will be carried out at three levels: a) To define the vitamin D metabolizing capability of human and lower animal hematopoietic cells: b) To specify the site and mechanism of action of our reported stimulation by recombinant Gamma-interferon of the 25(OH)-vitamin D3-1-hydroxylase in human pulmonary alveolar macrophages; and c) To specify the effects and to identify the mechanism of action of vitamin D metabolites on myeloid proliferation and function in vivo (D replete and deficient rats) and in vitro (stem cells from normal and leukemic subjects). These studies will be conducted with several differing myeloid cells including: (i) human pulmonary macrophages from normal subjects; (ii) cells from patients with possible dysfunctions of either the hematopoietic system (leukemia and human T lymphocyte leukemia virus, and HTLV induced leukemia, sarcoidosis, and hypercalcemia of malignancy) or (iii) vitamin D endocrine system (vitamin D-dependent rickets-II); (iv) human B and T lymphocyte cell lines infected with human T-cell leukemia virus; (v) murine peritoneal macrophages; and (vi) several chick acute myelogenous leukemic cell lines. Collectively these results will allow a precise formulation of the scope and details of the participation of vitamin D endocrinology in stem cell differentiation.
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