VITAMIN D RESISTANCE: MONKEY TO MAN

Cedars-Sinai Medical Center, West Hollywood CA

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Abstract

DESCRIPTION (provided by applicant): Primate species have developed to be the most biologically sophisticated organisms on our planet. Homo sapiens or man, has evolved from ancestral Old World primates inhabiting the African sub-continent and not from New World primates of South and Central America. In the Eocene 50-100 million years ago primordial primates in both the New and Old World were indistinguishable from one another, so why did man arise in the Old and not the New World? We propose that that the answer to this question is that New World primate species, unlike their Old World counterparts, were limited in geographic distribution to the periequatorial regions of the New World as a consequence of the acquired over-expression of a sub-family of nucleic acid binding proteins. These heterogeneous nuclear ribonucleoproteins (hnRNPs), at least one of which the vitamin D response element binding protein (VDRE-BP), competes in trans for binding to the vitamin D response element (VDRE) to squelch vitamin D receptor-directed transactivation. Although now known to be expressed in human as well as in subhuman primate cells, it was not previously known whether the hnRNP-related VDRE-BPs played a comparable role in gene expression in man. With the recent discovery of a human with hnRNP-mediated, VDR-RXR-normal, vitamin D resistance, it is now postulated that the family of hnRNP molecules can also serve as modulators of gene transcription and expression in man. In order to investigate this hypothesis three Specific Aims, representing a natural extension of our work from New World primates to man, will be undertaken: 1] Sequence, clone and functionally characterize the transcriptional squelching potential of the human vitamin D resistance-causing response element binding protein (REBiP); 2] perform forced overexpression of the human REBiP in mouse to recapitulate its capability to generate a rachitic phenotype in vivo; and 3] determine what effects the RNA-DNA binding actions of the human REBiP have on the splicing, processing, translation and function of VDR-regulated gene products. We expect to determine that the hnRNP-related REBiP represents 1] a novel paradigm for the means by which the cell's mRNA-making and -processing machines can be modulated by a single multi-functional protein and 2] a point of potential therapeutic intervention in the action of sterol/steroid hormones on their respective target cells.