: Complications of atherosclerosis continue to be the major causes of death in industrialized societies. Although cholesterol-lowering drugs can significantly reduce the risk of myocardial infarction in hypercholesterolemic patients, they are not sufficient to prevent the development of atherosclerosis in all high-risk individuals and there remains an urgent need for additional therapeutic approaches. The peroxisome proliferator-activated receptors (PPARs), and liver X receptors (LXRs) are nuclear hormone receptors that have recently been shown to exert both atherogenic and anti-atherogenic effects on patterns of gene expression. Based on the development of selective estrogen receptor modulators (SERMs) that exert estrogenic effects on some genes and anti-estrogenic effects on others, it may be possible to develop analogous modulators of PPARs and LXRs that selectively exert anti-atherogenic effects. Studies are proposed in this Unit to determine the molecular mechanisms by which SERMs exert selective effects on gene expression and to characterize the roles of specific co-activators and co-repressors in mediating the transcriptional activities of PPAR and LXRs alpha and beta.
Three specific aims are proposed.
Specific Aim 1 will test the hypothesis that SERMs exert anti-estrogenic or estrogenic effects depending on whether or not the nuclear receptor co-repressors N-CoR or SMRT are recruited to estrogen receptor target genes. An understanding of the molecular mechanisms responsible for the selective actions of SERMs is likely to facilitate the development of selective modulators of other classes of nuclear receptors.
Specific Aim 2 will investigate the roles of N-CoR and SMRT in mediating transcriptional repression and activation by LXRs. Preliminary studies suggest that activation of LXR target genes can be achieved by oxysterol-independent mechanisms that inhibit interactions between LXRbeta and N-CoR. These studies may suggest new strategies for development of selective LXR modulators.
Specific Aim 3 will investigate molecular mechanisms by which PPARgamma activates transcription of anti-atherogenic and atherogenic genes, focusing on the LXRalpha and CD36 genes as models. These studies will test the hypothesis that different co-activators are used to activate different PPARgamma target genes, providing an additional avenue for the development of selective modulators. In concert with collaborative efforts outlined in Units 2, 3, 4 and 5, these studies should provide significant new information on the roles of specific nuclear receptors in the development of atherosclerosis and the molecular mechanisms responsible for their actions. Insights derived from these studies may ultimately facilitate the development of novel drugs that can selectively modulate programs of gene expression to more effectively inhibit the development of atherosclerosis.
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