When compared to Old World primates, New World primates reared in captivity exhibit an inordinately high incidence of osteomalacia. The disease is characterized biochemically by a decrease in cellular content of the specific, high affinity receptor for 1,25-dihydroxyvitamin D3 (1,25-(OH)2-D3). This decrement in the functional intracellular receptor concentration for 1,25- (OH)2-D3, a phenomenon similar to that observed in some human subjects with vitamin D-dependent rickets, type II (VDDR-II), is compensated by maintenance of high circulating concentrations of 1,25-(OH)2-D3. The aims of the proposed research are threefold. The first objective is to establish the phylogenetic extent of the altered 1,25-(OH)2-D3-receptor interaction among simian and prosimian species in order to determine its origin in the primate branching sequence and to better understand factors responsible for the genesis of the alteration. The second objective is to characterize the compensatory measures that New World primates have adopted to maintain mineral ion homeostasis in the face of target cell "resistance" to the 1,25-(OH)2-D3 hormone. The third major objective is to identify the site(s) along the pathway of the intracellular mode of action 1,25-(OH)2-D3 that give rise to the altered hormone-receptor interaction in New World primates. In large part these objectives will be approached by comparative analysis of biochemical data obtained from cultured cells and small amounts of serum from New World primates, Old World primates, and prosimians; characterization of the New World primate receptor-1,25-(OH)2-D3 interaction will be examined with the aid of "intact cell" adn isolated receptor- hormone binding analysis, in vitro heterologous receptor-nucleus reconstitution experiments, immunoblot analysis of receptor with monoclonal antireceptor antibody, and quantitative bioassay of hormone-induced intracellular events. An exploration of the genetically altered 1,25-(OH)2-D3-receptor interaction in New World primates will expand our knowledge of the intracellular handling of 1,25-(OH)2-D3, lend insight into the fundamental similarities between the cellular action of sterol (1,25-(OH)2-D3) and steroid (glucocorticoids, sex steroids, and mineralocorticoids) hormones and perhaps provide a model system for the human disease, VDDR-II.