Steroid receptors regulate the expression of target genes involved in metabolism, development and reproduction. Steroid ligand hormones bind their cognate nuclear receptors and relocate to hormone response elements within target gene units. The activated receptors than accumulate coactivators which link them to the promoter complex and remodel chromatic locally. The p160/SRC family of coactivators appears to play a fundamental role in this regard. We hypothesize that individual coactivators for nuclear receptors have evolved as regulators of cellular metabolic pathways. Toward the goal of elucidating such pathways, we plan to carry out investigations of the genetic, regulatory and metabolic and metabolic functions of the SRC family of coactivators in vivo. We intend to (1) develop a genetic fingerprint of cellular expression (mRNA) and protein for the SRC family coactivators and determine the relative affinities of test receptors for these specific coactivators; (2) develop in vivo mouse models to understand the tissue preference of SRC family coactivators for estrogen (ER-alpha, ER-beta), progesterone and androgen receptors; (3) develop genetic fingerprints of downstream genes altered in specific and combinatorial Kos; and (4) do a thorough metabolic assessment of the effects of these co-activator alterations on carbohydrate and lipid metabolism in the mouse KO models. This information should lead to a greater understanding of steroid hormone tissue kinetics, individual phenotypic responses to hormones during development and following maturation, syndromes of partial hormone resistance, tissue-specific actions of Selective Receptor Modulators (SRMs), hormone-dependent cancers of breast, uterus and prostate, and the cross-communication of coactivators of cAMP/cytokine/Jak-State pathways which regulate carbohydrate metabolism, blood sugar levels, and lipid metabolism.
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