Nuclear Receptor Signaling Atlas: Opening Access to the Biology of Nuclear Receptor Signaling Pathways.

Signaling pathways involving nuclear receptors (NRs), their ligands and coregulators, regulate tissue-specific transcriptomes in diverse processes, including development, metabolism, reproduction, the immune response and neuronal function, as well as in their associated pathologies. The Nuclear Receptor Signaling Atlas (NURSA) is a Consortium focused around a Hub website (www.nursa.org) that annotates and integrates diverse 'omics datasets originating from the published literature and NURSA-funded Data Source Projects (NDSPs). These datasets are then exposed to the scientific community on an Open Access basis through user-friendly data browsing and search interfaces. Here, we describe the redesign of the Hub, version 3.0, to deploy "Web 2.0" technologies and add richer, more diverse content. The Molecule Pages, which aggregate information relevant to NR signaling pathways from myriad external databases, have been enhanced to include resources for basic scientists, such as post-translational modification sites and targeting miRNAs, and for clinicians, such as clinical trials. A portal to NURSA's Open Access, PubMed-indexed journal Nuclear Receptor Signaling has been added to facilitate manuscript submissions. Datasets and information on reagents generated by NDSPs are available, as is information concerning periodic new NDSP funding solicitations. Finally, the new website integrates the Transcriptomine analysis tool, which allows for mining of millions of richly annotated public transcriptomic data points in the field, providing an environment for dataset re-use and citation, bench data validation and hypothesis generation. We anticipate that this new release of the NURSA database will have tangible, long term benefits for both basic and clinical research in this field.

No time to lose: workshop on circadian rhythms and metabolic disease.

The objective of the workshop was to gain a better understanding of the link between circadian rhythms and human health and disease. The impacts of circadian rhythms on metabolic gene regulation, as well as the effect of nutrient uptake and balance on the molecular components of the clock, were discussed. Topics included the neural circuitry underlying the central clock; the effect of the environment and diet on the central clock as well as peripheral, tissue-specific clocks; and the transcriptional, post-transcriptional, and post-translational (e.g., epigenomic) mechanisms through which these signals are transduced. Evidence presented during the meeting demonstrated that circadian rhythms and metabolism are intricately linked, and that disruption in these rhythms have profound consequences-many times leading to metabolic disease. The mechanisms by which circadian rhythms are maintained and the cross-talk with metabolic signaling are just beginning to be elucidated. However, the interactions between these fields and the knowledge learned will clearly have a profound impact on our understanding of metabolic disease and lead to novel therapeutic approaches in the future.

The nuclear receptor superfamily of steroid hormones and vitamin D gene regulation. An update.

Nuclear receptors bind to chromatin and seed formation of complexes comprising coregulators at the hormone response element. Nuclear receptors and coregulators can mediate chromatin remodeling, epigenetic modification, and ultimately gene expression. Chromatin immunoprecipitation has shown that nuclear receptors bind to chromatin throughout the genome, often at locations distant from the transcription start site. New findings related to the regulation of key vitamin D target genes in intestine and bone as well as nonclassical actions of 1,25-dihydroxyvitamin D(3)[1,25(OH)(2)D(3)], including effects on breast cancer cells and on the immune system, are discussed. These studies will form the basis for future studies examining global networks regulated by the vitamin D receptor. It is becoming increasingly recognized that the actions of 1,25(OH)(2)D(3), similar to those of other steroids, is complex, involving regulation of gene activity at a range of locations.

Chemical approaches to nuclear receptors in metabolism.

The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) sponsored a workshop, "Chemical Approaches to Nuclear Receptors and Metabolism," in April 2009 to explore how chemical and molecular biology and physiology can be exploited to further our understanding of nuclear receptor structure, function, and role in disease. Signaling cascades involving nuclear receptors are more complex and interrelated than once thought. Nuclear receptors continue to be attractive targets for drug discovery. The overall goal of this workshop was to identify gaps in our understanding of the complexity of ligand activities and begin to address them by (i) increasing the collaboration of investigators from different disciplines, (ii) developing a better understanding of chemical modulation of nuclear receptor action, and (iii) identifying opportunities and roadblocks in the path of translating basic research to discovery of new therapeutics.

Minireview: Evolution of NURSA, the Nuclear Receptor Signaling Atlas.

Nuclear receptors and coregulators are multifaceted players in normal metabolic and homeostatic processes in addition to a variety of disease states including cancer, inflammation, diabetes, obesity, and atherosclerosis. Over the past 7 yr, the Nuclear Receptor Signaling Atlas (NURSA) research consortium has worked toward establishing a discovery-driven platform designed to address key questions concerning the expression, organization, and function of these molecules in a variety of experimental model systems. By applying powerful technologies such as quantitative PCR, high-throughput mass spectrometry, and embryonic stem cell manipulation, we are pursuing these questions in a series of transcriptomics-, proteomics-, and metabolomics-based research projects and resources. The consortium's web site (www.nursa.org) integrates NURSA datasets and existing public datasets with the ultimate goal of furnishing the bench scientist with a comprehensive framework for hypothesis generation, modeling, and testing. We place a strong emphasis on community input into the development of this resource and to this end have published datasets from academic and industrial laboratories, established strategic alliances with Endocrine Society journals, and are developing tools to allow web site users to act as data curators. With the ongoing support of the nuclear receptor and coregulator signaling communities, we believe that NURSA can make a lasting contribution to research in this dynamic field.

The Nuclear Receptor Signaling Atlas: catalyzing understanding of thyroid hormone signaling and metabolic control.

The Nuclear Receptor Signaling Atlas (NURSA) was established as a trans-National Institutes of Health resource to develop, accrue, and communicate information about the nuclear receptor (NR) superfamily of ligand-dependent and -independent transcription factors. NRs have broad involvement in the regulation of development, reproduction, and metabolism. Receptors for thyroid hormones represent important members of the NR superfamily with key roles in development and homeostasis. NURSA has attempted to create a resource for information on NRs, associated coregulators, and ligands. The Web portal (www.NURSA.org) creates a window through which the general research community can gain access to data generated by NURSA investigators and linked from other sources. The molecule pages provide detailed curated information about the NR superfamily and allow the user to search for information useful to their own specific research problems. With the application of bioinformatics solutions, analyses of large amounts of data can be utilized to validate and/or create hypotheses that will ultimately lead to translational opportunities to take information about NRs, in general, and thyroid receptors, in particular to potential clinical applications.

Nuclear receptors and bone.

Nuclear receptors (NRs) represent a class of ligand-dependent and -independent transcription factors with importance to the regulation of development, reproduction, and metabolism. The emergence of new understanding of the structure, function, and role in disease of NRs provides new insights into the interaction between genetics and the environment, with NRs representing new targets for the development of therapeutic agents. NRs play key roles in bone health and contribute to our understanding of diseases and disorders that result in osteopenia and osteoporosis. The Nuclear Receptor Signaling Atlas (http://www.nursa.org) is an online repository of information about NRs and provides a community-wide resource designed to help catalyze new advances in biology and medicine.

Novel targets and therapeutics for bone loss.

Advances in the treatment of osteoporosis over the past decade have resulted in the generation of novel therapeutic agents aimed at providing both anticatabolic and anabolic effects in bone. In-depth understanding of the biology of key factors regulating bone metabolism has begun to reveal new approaches to treating this costly and debilitating disease. During the next decade we will observe the development and evolution of several new classes of therapeutic targets and agents to combat this disease.

The Nuclear Receptor Signaling Atlas: development of a functional atlas of nuclear receptors.

The Nuclear Receptor Signaling Atlas (NURSA) was developed by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institute on Aging (NIA), and the National Cancer Institute (NCI) of the National Institutes of Health (NIH); the aim of NURSA is to utilize classical approaches to validate existing hypotheses and exploit new and emerging technologies to formulate and test new hypotheses that might elucidate the program of nuclear receptor (NR) structure, function, and role in disease. The means for carrying out this ambitious program required development of interactions among investigators and the combined application of new high-throughput technologies and existing approaches to allow for both mechanistic studies and accrual of large datasets in a discovery-based research effort, all leading to advances with implications for the missions of the NIDDK, NIA, and NCI. A team-based multidisciplinary approach has allowed for both objectives to proceed simultaneously, tied together via a central bioinformatics resource and one web-accessible venue (www.nursa.org). The ultimate goals for the NURSA consortium are to: 1) establish the mechanistic principles of NR function, 2) characterize NR-coregulator complex formation and regulation, 3) map protein-protein interactions for coregulators, 4) identify candidate downstream target genes of NR action, 5) identify target tissue expression of NRs, 6) understand the regulation of NR expression and, 7) integrate existing and emerging information through NURSA bioinformatics tools.