The classical models of progesterone action held that the biological activities of progestins and antiprogestins are mediated through a specific high-affinity receptor protein located in the nuclei of target cells. According to this model, upon agonist binding the progesterone receptor (PR) is converted into a transcriptionally-active form and antagonists manifest their activity by competitively blocking agonist access to the receptor. This relatively simple model has become more complex with the discovery that this receptor can exist in either of two functionally-distinct forms within target cells: hPR-A and hPR-B. The additional finding that the classical role of a ligand as a molecular switch, converting PR from an inactive to an active form, does not adequately describe the pharmacology of the known PR-ligands. In the last funding period, we focused on these two aspects of PR-action and determined that the A and B forms of this receptor have distinct, opposing roles. Specifically, it was found that hPR-B is an activator of progesterone-responsive genes in most cells, whereas hPR-A is a ligand-dependent inhibitor of hPR-B function. It was demonstrated also that agonist- or antagonist-activated hPR-A can modulate the ability of cells to respond to estrogens, androgens, glucocorticoids and mineralocorticoids, suggesting that hPR-A is a key point of convergence between these signaling systems. The pharmacology of PR was compounded further upon the observation that different ligands have different effects on PR-structure, and that cells possess machinery to distinguish between these structurally- distinct complexes. Dissection of the molecular basis for this selectivity has enabled us to identify a novel class of selective progesterone receptor modulators (SPRMs) which function as agonists in some environments and antagonists in others. We propose, therefore, in the upcoming funding period, to focus on defining the mechanisms underlying the differential transcriptional activity of hPR-A and hPR-B and the means by which the activities of these receptors are influenced by ligands. Reflecting these overall objectives and taking into consideration our preliminary data, we propose the following specific aims:(1) Identification and characterization of peptides which interact with agonist or antagonist activated hPR-A or hPR- B. (2) Development and use of peptide antagonists of hPR-A and hPR-B to identify isoform-specific biological activities. (3) Definition of the molecular mechanism of action of the selective progesterone receptor modulators (SPRMs). (4) Identification of cellular factors which modulate PR-pharmacology.
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