This award supports cooperative research on steroid hormones to be conducted by Anthony Norman of the University of California at Riverside and his Argentine colleague R. Boland of the National University of the South in Bahia Blanca, Argentina. They propose a collaborative research program directed towards studies on the biochemical mode of action of the hormonally active form of vitamin D. While it is generally accepted that steroid hormones generate biological responses through regulation of gene expression, it is not widely accepted that steroid hormones can generate significant biological responses through mechanisms not dependent upon immediate regulation of gene expression. Both laboratories have published a series of papers reporting that 1,25(OH)2D3 can generate biological responses in muscle (Bahia Blanca) and the intestine (Riverside) by nuclear receptor-mediated modulation of gene expression as well as by a pathway(s) in which a putative membrane recognition element for 1,25(OH)2D3 is implicated in processes which generate biological responses within 1-5 minutes. The major objectives of this proposal are (a) to initiate a collaborative characterization of the membrane-related receptor for 1,25(OH)2D3 in intestine, HL-60 cells and muscle and compare it with the classical nuclear receptor for 1,25 (OH)2D3 and (b) further define the biochemical details of the signal transduction pathway leading to "rapid" biological responses which lead in the intestine to the process of "transcaltachia" or the very rapid stimulation of intestinal calcium absorption. Specifically the Riverside laboratory will study the role of 1,25(OH)2D3 receptors in (a) gene expression particularly as exemplified by examination of the calbindin-D28K gene's promoter and (b) the process of transcaltachia or the very rapid stimulation of intestinal calcium transport (via nongenomic mechanisms). The Bahia Blanca laboratory will study the function and mechanism of action of 1,25(OH)2D3 and its receptor(s) in muscle. This work will formalize an existing active collaboration.
