ORPHAN & NUCLEAR RECEPTORS: Strategies for New Therapeutic InterventionsJune 27 - 28, 2002 • Holiday Inn On The Bay • San Diego, CA USA [ Overview | Agenda | Call for Posters | Register ] View Electronic Brochure (PDF)Overview
Featuring: Post - Conference Half-Day Workshop : Main Conference: Due to the significant physiological role, nuclear and orphan receptors are emerging targets for drug discovery beyond functioning as transcription factors. Enhancing or inhibiting the effect of nuclear receptors or structural changes of their ligands is of significant importance. This has a tremendous influence on the metabolic pathways of diseases such as diabetes, heart diseases or cancer. A greater understanding of nuclear receptors and their interactions is important for developing drugs with fewer side effects. This conference will discuss the effects of nuclear receptors in lipid metabolism, the role of orphan receptors in xenobiotic metabolism and the relationship between nuclear receptors and tumor cells. Furthermore, the newest developments on receptor modulators and co-activators will be presented. International experts from industry and academia provide you with the latest findings on: - PPAR and Atherosclerosis
Medical Engineering and Physics from Elsevier Science Journal of Orthopaedic Research from Elsevier Science AgendaThursday, June 27, 20028:15 Registration, Poster/Exhibit Set Up, Coffee & Pastries 8:55 Chairperson's Opening Remarks Lipid metabolism9:00 27-Hydroxycholesterol: An Endogenous LXR Ligand Cholesterol loading of many different cell types results in an increased expression of LXR-responsive genes, though cholesterol itself is not an LXR ligand. Here we demonstrate a role for 27-hydroxycholesterol, a ubiquitously formed metabolite of cholesterol, as an endogenous ligand of LXR mediating the cholesterol overload response. This finding may explain some of the clinical features of sterol 27-hydroxylase deficiency (CTX). 9:30 Effects of PPARs In Animal Disease Models of Insulin Resistance and Dyslipidemia Insulin resistance and dyslipidemia are key disorders in a variety of metabolic diseases, including metabolic syndrome, impaired glucose tolerance and type 2 diabetes. PPARa and PPARb are important regulators of lipid/lipoprotein and carbohydrate metabolism in man while the role of PPARd is unclear. This talk will provide an overview of the effects of each PPAR subtype in rodent and primate animal disease models of insulin resistance and dyslipidemia. 10:00 The Role of PPARs in the Development of Atherosclerosis Atherosclerosis is a leading cause of morbidity and mortality in Western Societies and is a major complication of diabetes. Thiazolidinediones, a class of insulin-sensitizing drugs, are synthetic ligands for PPAR g. It has been shown that activation of PPARg modulates genes involved in the development of atherosclerosis. In addition, two other forms of PPAR, alpha and delta, are also found in macrophages, as well as endothelial and smooth muscle cells. Using the Low density lipoprotein receptor-deficient mouse model, we studied the effects of all three PPARs on the development atherosclerosis. 10:30 Refresment Break and Poster/ Exhibit Viewing 11:00 Nuclear Receptor Signaling Pathways in Atherosclerosis The nuclear receptors PPAR and LXR are important regulators of lipid metabolism in multiple tissues including adipose tissue, liver and macrophages. Macrophage uptake of oxidized low-density lipoprotein (oxLDL) is central to the pathogenesis of atherosclerosis. Recent work indicates that ligand activation of members of the nuclear receptor superfamily by oxidized lipids may play an important role in the control of macrophage gene expression. Following receptor-mediated endocytosis into macrophages, the oxLDL particle can serve as a source of ligand for two different groups of nuclear receptors, the PPARs and LXRs. We have shown that PPARg links macrophage lipid uptake to a pathway for reverse cholesterol transport. PPARg induces ABCA1 and apolipoprotein E (apoE) expression and cholesterol removal from macrophages through a transcriptional cascade involving the nuclear receptor LXRa. Ligand activation of PPARg leads to primary induction of LXRa and to coupled induction of ABCA1 and apoE. Thus, nuclear receptors coordinate a complex physiologic response to oxLDL that involves particle uptake, processing and cholesterol removal through ABCA1 and apoE. Transplantation of PPARg or LXR null bone marrow into apoE-/- or LDLR-/- mice leads to a significant increase in atherosclerosis. These observations identify PPARg and the LXRs as endogenous inhibitors of atherosclerosis and potential targets for therapeutic intervention in cardiovascular disease. Orphan Receptors and Xenobiotics11:30 SXR: A Sensor and Coordinate Regulator of Xenobiotic Clearance SXR has been shown to be a xenobiotic and bile acid sensor and to play a key role in regulating drug metabolism in the liver. We will discuss recent work describing novel functions for this nuclear receptor as it relates to overall xenobiotic metabolism and clearance. 12:00 Nuclear Receptor CAR in Adaptive Expression of Genes in Response to Drugs The nuclear receptor CAR was first implicated as a key transcription factor that regulates induction of CYP2B by phenobarbital (PB). DNA microarray has now shown that CAR regulates CYP3A, CYP reductase, and various transferases in mouse liver. CAR has also played roles in the repression of enzymes involved in fatty acid oxidation as well as in the blocking of PB induction of enzymes responsible for lipid peroxidation. CAR does not regulate all PB responses: for example, the induction of amino levulinate synthase 1 is not under CAR regulation.Thus, liver cells are endowed with multiple mechanisms to allow the cells to alter the expression of genes to confer adaptive capabilities in response to PB exposure. 12:30 Functional Role of RXRa in Hepatocyte: From Fatty Acid, Carbohydrate to Xenobiotic Metabolism A large number of physiological processes in the adult liver are regulated by nuclear receptors that require heterodimerization with retinoid x receptors (RXRs). We have used cre-mediated recombination to disrupt the RXRa gene in mouse hepatocytes. Although such mice are viable, molecular and biochemical parameters indicate that fatty acid, carbohydrate, cholesterol, and xenobiotic metabolic pathways are compromised in the mutant male mice. 1:00 Luncheon, sponsored by The Knowledge Foundation 2:25 Chairperson's Remarks Receptor Modulators and Co-regulators2:30 Different Conformations of the Steroid Hormone 1,25(OH)2-vitamin D3 Act as Optimal Ligands for the VDRnuc (genomic responses), the VDRmem (Rapid Responses) and the Vitamin D-binding protein (DBP) The steroid hormone 1,25(OH)2D3 is conformationally flexible (side chain, seco B-ring and A-ring) and accordingly is able to generate a large array of different shapes to serve as optimal ligands for the two receptors for 1,25(OH)2D3, the nuclear receptor (VDRnuc; genomic responses) and the putative membrane receptor (VDRmem; rapid responses) and for the vitamin D-binding protein (DBP; plasma transport of D-metabolites). This presentation will review and contrast several case studies for the VDRnuc, the VDRmem and DBP illustrating the importance of a given preferred ligand shape for the biological outcome of the protein's function. 3:00 Nonsteroidal Progesterone Receptor Modulators From Fungal Metabolite We discovered novel nonsteroidal progesterone receptor modulators, PF1092 substances, from fungal fermentation broth and synthesized a lot of derivatives from PF1092C. Some of them possess good affinity and selectivity for progesterone receptors, and show antagonist or mixed agonist-antagonist activity in vitro and in vivo. We now show the structure-activity relationship and the pharmacology of our nonsteroidal progesterone receptor modulators. 3:30 Refreshment Break and Poster/ Exhibit Viewing 4:00 New Models to Assess the Activity of Progesterone Receptor Modulators Progesterone plays an important role in female reproduction. Here we report the development of two models to assess the activity of progesterone receptor (PR) modulators in rats. In the first model an estrogen is used to stimulate complement component C3 expression in the uterus with progestin co-administration inhibiting this effect. Progesterone, MPA and a new progestin, trimegestone have been characterized in this model as have PR antagonists. The second model involves the identification of several genes that are regulated by MPA in the mammary gland that can serve as molecular markers for progestin action such as casein kinase II which serves as an excellent marker of progestin-stimulated cell proliferation.
Nuclear receptors play a key role in the etiology of many human diseases. We have focused on the regulation of neuronal cell development and lipid metabolism for developing integrated cellular and biochemical assays that can target nuclear receptors as an entire gene family. The developed strategies and results obtained from using the assays as screening tools will be discussed as part of an overall drug discovery platform. 5:00 Engineering Orthogonal Ligand-Receptor Pairs from Nuclear Receptors and "Near Drugs" To create orthogonal ligand-receptor pairs to control transcription, site-directed mutagenesis was used to generate retinoid X receptor (RXR) variants. Mutated residues in RXR were chosen from structural analysis of RXR and the retinoic acid receptor (RAR) ligand binding domains. The potential ligands screened for activation of variant receptors are "near drugs"- compounds synthesized during structure-activity studies that are structurally similar to an approved drug yet inactive on the wild-type receptor. 5:30 End of Day One Friday, June 28, 20028:15 Coffee and Pastries and Poster/ Exhibit Viewing 8:55 Chairperson's Opening Remarks Receptor Modulators and Co-regulators9:00 Cell-Specific Expression of Nuclear Receptor Coactivator GT198 in Mouse Embryo and Human Cancers GT198 is a nuclear receptor coactivator that interacts with the DNA-binding domain of nuclear receptors, and potently stimulates nuclear-receptor mediated transcription activation. GT198 is highly expressed in spermatocytes of adult testis, but is almost absent in the remainder of adult tissues. In addition, the expression of GT198 is up-regulated during embryonic development and in a subset of human cancers. 9:30 Orphan Nuclear Receptors, Transcriptional Regulation and Drug Discovery Nuclear receptors are ligand-activated transcription factors and have been associated with cancer, autoimmune, metabolic, cardiovascular and CNS diseases. Orphan nuclear receptors belong to this gene super family but with unknown ligands, target genes and physiological function. X-Ceptor has established a drug discovery program that vertically integrates these targets with a goal of understanding their function as regulatory proteins and to exploit the therapeutic opportunities for a wide variety of biological processes. Our platform includes chemistry, pharmacology, genomics and receptor biology and is focused on creating powerful tools that elucidate the biology of the individual orphans and allow the discovery of small-molecule therapeutics to treat the related diseases. We have applied this paradigm in the discovery of novel pathways mediated by these nuclear receptors, including LXR and FXR, and have been successful in identifying potent, selective and efficacious small-molecule lead compounds to modulate these pathways. Nuclear Receptors and Cancer10:00 Selective Retinoids and Their Use in Cancer Therapy Over the last decade, numerous studies have established the activity of the retinoids as key modulators of cell growth, differentiation and apoptosis. Moreover, a large number of reports have described the tumor-suppressive effect of the retinoids and have attributed this activity in part to the RAR( family member which has been identified as a key player in retinoid-induced cell growth arrest. One aspect of our studies was to develop a/b selective agonists with anti-cancer efficacy and reduced toxicity associated with RARg activity. A second focus was to evaluate the potential use of RXR selective agonists as differentiating agents of breast tumor cells. 10:30 Refreshment Break and Poster/Exhibit Viewing 11:00 Mechanism of Action and Biological Functions of the Retinoid-Related Orphan Receptor ROR The retinoid-related orphan receptor g ( RORg ) is essential for lymph node development and plays an important role in maintaining homeostasis in the thymus. Mice deficient in RORg are highly susceptible to developing malignant T-cell lymphomas. Loss of RORg expression disturbs homeostasis in the thymus by enhancing apoptosis and proliferation. These observations suggest a role for RORg in oncogenesis. 11:30 Tissue Expression and Potential Role of LXRa and FXR In Neoplastic Tissues and Tumour Derived Cell Lines The orphan nuclear receptors LXRa and FXR have recently been shown to control a number of genes involved in bile acid and lipid metabolism. The role played by other orphan nuclear receptors such as RAR, RXR and PPARs in cell differentiation and proliferation is well established. LXRa and FXR might display similar activities and modulators of these receptors might be useful in the treatment of neoplastic diseases. The current status of studies on the expression of LXRa and FXR in normal, neoplastic tissues and tumour derived cell lines will be reviewed. The functional relationship between the expression these receptors, cell differentiation and malignancy will be discussed. 12:00 End of Conference Post - Conference Half-Day Workshop |
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Registration fee includes lunch on the first day, refreshments and all documentation made available to us by speakers. Commercial registration: Academic/government registration: Posterboard fee: US $45 (you must be registered) The academic/government rate is extended to all participants registering as full time employees of government and universities. To receive the academic/government rate you must not be affiliated with any private organizations either as consultants or owners or part owners of businesses. Payment: All payments must be made in U.S. funds drawn on a U.S. bank. Please make check(s) payable to The Knowledge Foundation, Inc. and attach to the registration form even if you have registered by phone, fax or e-mail. To guarantee your registration, payment must be received prior to the conference. Confirmation of your booking will follow. Discount Accommodations and Travel: A block of rooms has been allocated at a special reduced rate. Please make your reservations by May 20, 2002. When making reservations, please refer to The Knowledge Foundation. Contact The Knowledge Foundation if you require assistance. Venue: For Hotel Reservations Contact: Substitutions/Cancellations: A substitute member of your company may replace your attendance at any time at no charge if you find your schedule prevents you from attending. Please notify us immediately so that materials can be prepared. If you do not wish to substitute your registration, we regret that your cancellation will be subject to a $100 processing fee. To receive a prompt refund, we must receive your cancellation in writing 15 days prior to the conference. Unfortunately cancellations cannot be accepted after that date. In the event that The Knowledge Foundation, Inc. cancels an event, The Knowledge Foundation, Inc. cannot resume responsibility for any travel-related costs. |
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