Ronald N. Margolis

The National Institutes of Health's Big Data to Knowledge (BD2K) initiative: capitalizing on biomedical big data

Biomedical research has and will continue to generate large amounts of data (termed ‘big data’) in many formats and at all levels. Consequently, there is an increasing need to better understand and mine the data to further knowledge and foster new discovery. The National Institutes of Health (NIH) has initiated a Big Data to Knowledge (BD2K) initiative to maximize the use of biomedical big data. BD2K seeks to better define how to extract value from the data, both for the individual investigator and the overall research community, create the analytic tools needed to enhance utility of the data, provide the next generation of trained personnel, and develop data science concepts and tools that can be made available to all stakeholders.

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 consortiums 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 superfamily of steroid hormones and vitamin D gene regulation

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 D3[1,25(OH)2D3], 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)2D3, similar to those of other steroids, is complex, involving regulation of gene activity at a range of locations.

Nuclear Receptor Signaling Atlas (www.nursa.org): hyperlinking the nuclear receptor signaling community

The nuclear receptor signaling (NRS) field has generated a substantial body of information on nuclear receptors, their ligands and coregulators, with the ultimate goal of constructing coherent models of the biological and clinical significance of these molecules. As a component of the Nuclear Receptor Signaling Atlas (NURSA)—the development of a functional atlas of nuclear receptor biology—the NURSA Bioinformatics Resource is developing a strategy to organize and integrate legacy and future information on these molecules in a single web-based resource (). This entails parallel efforts of (i) developing an appropriate software framework for handling datasets from NURSA laboratories and (ii) designing strategies for the curation and presentation of public data relevant to NRS. To illustrate our approach, we have described here in detail the development of a web-based interface for the NURSA quantitative PCR nuclear receptor expression dataset, incorporating bioinformatics analysis which provides novel perspectives on functional relationships between these molecules. We anticipate that the free and open access of the community to a platform for data mining and hypothesis generation strategies will be a significant contribution to the progress of research in this field.

Mutations in the insulin receptor gene in genetic forms of insulin resistance.

Publisher Summary This chapter discusses the mutations in the insulin receptor gene that have been identified in patients with genetic forms of insulin resistance. Two clinical features are commonly observed in patients with extreme insulin resistance irrespective of the biochemical mechanism which causes the insulin resistance: (1) acanthosis nigricans, which is a hyperkeratotic hyperpigmented skin lesion, and (2) hyperandrogenism, which is a clinical sign that is commonly observed in premenopausal women with extreme insulin resistance as a result of increased ovarian production of testosterone. The pathway of insulin receptor biosynthesis is complex and involves transcription of the gene, translation of the mRNA, and multiple posttranslational modifications. After the completion of biosynthesis, the mature receptor molecule is transported to the cell surface for insertion into the plasma membrane. Defects have been described that impair many of these steps and thereby lead to reduction in the number of insulin receptors on the cell surface. The chapter explains clinical syndromes of extreme insulin resistance. The chapter discusses two types of syndromes: (1) genetic type A insulin resistance including lipoatrophic diabetes, leprechaunism, and Rabson–Mendenhall and (2) autoimmune type B insulin resistance.

Novel Targets and Therapeutics for Bone Loss

Abstract:  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.

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.

Chemical Approaches to Nuclear Receptors in Metabolism

An NIH-sponsored workshop focused on innovative chemical methods for probing and modulating nuclear receptor pathways. 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.

Nuclear Receptors and Bone

Abstract:  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.

Commentary: Parallel Evolution of Molecular Endocrinology as a Journal and a Discipline: Convergence of Interests with the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK/NIH)

The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) celebrates in 2010 its 60(th) year as an institute of the National Institutes of Health. NIDDK has been fundamental in providing support for research in endocrinology, fostering research to elucidate basic principles of endocrine signaling leading to understanding of diseases and disorders of hormone action. Over this time span, a move to a more molecular level in understanding of the basis of hormone action has emerged and been supported by NIDDK, with many advances finding their way into a new journal, Molecular Endocrinology. The merging of disciplines that has made this possible constitutes a major force for further progress as NIDDK moves forward over the next 60 yr. Together, NIDDK and Molecular Endocrinology have served as catalysts for advancing knowledge in the field, energizing new paradigms that have led to advances in the clinic.