Most human diseases involve interactions between genetic and environmental factors. Although the environment is implicated in most chronic diseases, the etiology and mechanisms of action underlying these diseases remain unclear. It is estimated that more than 80,000 chemicals are currently used in commerce, challenging elucidation about chemical mechanisms-of-action and prioritization of environmental health research. Integration of diverse data with novel analysis approaches is required to understand environment-disease associations, mechanistic pathways of toxicity, risk assessment, regulation, and development of effective therapeutic interventions. In 2004, the Comparative Toxicogenomics Database (CTD; http://ctdbase.org) was launched publicly to address an unmet need for a public data resource dedicated exclusively to advancing understanding about environment-disease connections. Today, through diversified funding approaches and in response to the evolving needs of the environmental health research community, CTD provides a combination of richly annotated data describing chemical-gene-disease networks, exposure information, phenotype data, and novel analysis tools that enable user-driven discoveries about environmental influences on human health. This proposed project will enable the continued development and expansion of this resource for the environmental health and biomedical research community.

Per- and polyfluoroalkyl substances (PFAS) are emerging as a major public health problem in North Carolina and across the United States. PFAS comprise a class of over 5,000 compounds. Their unique chemical properties have been harnessed to make consumer and industrial products more water, stain, and grease resistant; they are found in products as diverse as cosmetics and flame-retardants. PFAS are resistant to degradation, move easily through the environment, and accumulate in living organisms. Exposure to PFAS has been associated with health effects including cancer and toxicity to the liver, reproductive development, and thyroid and immune systems. Despite widespread detection in the environment and evidence of increasing human exposure, understanding about PFAS toxicity, its bioaccumulative potential in dietary sources such as aquatic organisms, and effective remediation remain notably understudied. The recent discovery by this proposed Center������������������s Deputy Director, Dr. Detlef Knappe, of widespread PFAS contamination in the Cape Fear River watershed in NC underscores that these compounds are in need of immediate investigation.. The goal of our Center is to advance understanding about the environmental and health impacts of PFAS. To meet this goal we are employing a highly trans-disciplinary approach that will integrate leaders in diverse fields (epidemiology, environmental science and engineering, biology, toxicology, immunology, data science, and advanced analytics); all levels of biological organization (biomolecule, pathway, cell, tissue, organ, model organism, human, and human population); state-of-the-art analytical technologies; cutting-edge data science approaches; a recognized track record in interdisciplinary, environmental health science (EHS) training; and well-established partnerships with government and community stakeholders.

The mission of the Center for Human Health and the Environment (CHHE) is to advance understanding of environmental impacts on human health. Through a systems biology framework integrating all levels of biological organization, CHHE aims to elucidate the fundamental mechanisms through which environmental exposures/stressors interface with biomolecules, pathways, the genome, and epigenome to influence human disease. CHHE will develop three interdisciplinary research teams that represent NC State������������������s distinctive strengths. CHHE will implement specific mechanisms to promote intra- and inter-team interactions and build interdisciplinary bridges to advance basic science discovery and translational research in environmental health science along the continuum from genes to population. These teams are; - The Molecular/Cellular-Based Systems and Model Organisms Team will utilize cutting edge molecular/cellular-based systems and powerful vertebrate and invertebrate model organisms to define mechanisms, pathways, GxE interactions, and individual susceptibility to environmental agents. - The Human Population Science Team will integrate expertise on environmental exposures, epidemiology, genomics and epigenomics to identify key human pathways and link exposure and disease across populations. - Bioinformatics Team will develop novel analytics and computational tools to translate Big Data generated across high-throughput and multiscale experiments into systems-level discoveries To further increase the impact and translational capacity of these teams, CHHE will develop three new facility cores that will provide instrumentation, expertise, and training to facilitate basic mechanism- to population-based research. - The Integrative Health Sciences Facility Core will expand the ability of CHHE members to translate basic science discoveries across species and provide mechanistic insights into epidemiological studies by partnering with: a) NC State������������������s Comparative Toxicogenomics Database (CTD); b) East Carolina University Brody School of Medicine and c) NC Dept. of Health and Human Services. - The Comparative Pathobiology Core will be located at NC State������������������s top-ranked College of Veterinary Medicine and its nationally recognized veterinary pathology group to facilitate assessment of the effects of environmental stressors in the many model organisms utilized by CHHE members. - The Systems Technologies Core will introduce state-of-the-art proteomics capabilities and dedicated bioinformatics support to expand the ability of CHHE members to analyze the Next Generation Sequencing data involving the genome, transcriptome and epigenome. As a land-grant university, NC State has an extensive and active Cooperative Extension Service network throughout North Carolina. CHHE will utilize this unique network to develop a highly effective, multi-directional Community Outreach and Engagement Core to disseminate findings that will contribute to addressing disparity in exposures and health outcomes and to educate communities about environmental influences on health. A strong Career Development Core for early stage scientists that is coordinated with a robust Pilot Project Program will support cutting-edge, collaborative and multidisciplinary environmental health projects to enhance the research success and impact of our membership. Through these activities and the purposeful interfacing of different disciplines CHHE will build on NC State������������������s unique research and community outreach strengths to become a premier transformative and synergistic EHS Core Center.

This three-day conference on ����������������Highly Fluorinated Compounds ������������������ Social and Scientific Discovery��������������� will examine the complex set of social, scientific, political, and environmental health issues raised by the recent discoveries of water contamination with high levels of highly fluorinated compounds. By bringing together scientists, government officials, activists, lay people, journalists, and lawyers, the conference can build on the diverse experiences and perspectives in order to better understand issues of science, regulation, remediation, prevention, and community engagement.

The Comparative Toxicogenomics Database is the only publicly available database providing curated data describing molecular mechanisms of action of chemicals and their disease relationships. This grant is in a NCE - with the Mount Desert Island Biological Laboratory as the host institution (but Carolyn Mattingly here at NCSU is the PI). This record is requesting submission of a request for transfer of the grant from MDIBL to NCSU as soon as possible to enable submission of a competititive renewal in July 2016 with NCSU as the host institution.

The long-range goal of the proposed project is to provide a centralized, freely available resource with comprehensive, well-annotated data and analysis tools that informs hypothesis development and interpretation of environmental health studies and promotes understanding about the etiologies of environmental diseases. Most human diseases involve interactions between genetic and environmental factors. The environment is implicated in many common conditions such as asthma, cancer, and diabetes; however, the etiology of these widespread diseases remains unclear. More than 85,000 chemicals are currently used in commerce, challenging elucidation about chemical mechanisms of action and prioritization of environmental research. Integration of critical data with novel analysis approaches is required to understand environment-disease associations and is essential for improving toxicity prediction, risk assessment, regulation and development of effective therapeutic interventions. We developed the freely available Comparative Toxicogenomics Database (CTD; http://ctd.mdibl.org) to address this need. CTD provides manually curated data describing cross-species chemical-gene interactions and chemical- and gene-disease relationships from the peer-reviewed literature and integrates this information with select external data sets (e.g., molecular pathways) and novel analysis tools. In this application we propose to: 1) comprehensively curate chemical-gene-disease interactions and expand the scope of phenotype curation to include cellular and diverse organism effects that will enable users to: a) identify biomarkers of environmentally influenced diseases and b) infer potential human health consequences from toxicological studies in model organisms and in vitro studies; and 2) design and implement new tools to facilitate development, analysis and interpretation of novel hypotheses focused on chemical-gene-disease interaction networks. This proposed project will leverage our cutting-edge software development, curation expertise and well-established, flexible infrastructure to facilitate increased understanding of critical environmental health issues in direct alignment with emerging research priorities.

Cadmium (Cd) is an extremely toxic industrial and environmental pollutant classified as a human carcinogen. It is a metal found ubiquitously in the earth������������������s crust and extracted in the production of other metals such as copper, lead, and zinc. Human exposure occurs through consumption of contaminated food, cigarette smoke, and fossil fuel combustion. Cd is associated with nephro-, neuro-, and osteotoxicicity, and carcinogenesis. Animal and epidemiological studies have linked exposure to learning disabilities, autism spectrum disorders (ASD), and hyperactivity. Unlike other toxic heavy metals, Cd is not thought to directly damage DNA. Instead toxicity may occur through epigenetic changes, such as altered DNA methylation or chromatin modification, although the mechanisms remain unclear. Given the ubiquitous presence of cadmium and the increasing prevalence of ASD and associated conditions such as attention deficit hyperactivity disorder, improved understanding of Cd������������������s mechanism of action and potential role in the etiology of these disorders is critical. Our laboratory uses the zebrafish as a powerful comparative model to explore conserved mechanisms underlying environmentally influenced phenotypes. Our preliminary data indicate that developmental exposure to cadmium in zebrafish results in hyperactivity and significant (>five-fold) downregulation of the ring finger protein 2 (Rnf2; previously Ring1b), which is an E3 ubiquitin ligase and a major regulator of chromatin structure via ubiquitination of histone H2A, as it is a subunit of the polycomb repressive complex 1. In addition, hyperactivity was recapitulated in Rnf2 heterozygous knockout fish as well as in wildtype fish exposed to an Rnf2 specific inhibitor, indicating that levels of Rnf2 protein are a critical factor in the observed hyperactivity. Based on these findings, we hypothesize that downregulation of Rnf2 coupled with altered chromatin structure may play an important role in Cd-mediated hyperactivity. To probe this hypothesis, we will explore two fundamental questions: 1) does restoration of Cd-mediated downregulation of Rnf2 rescue exposure-related hyperactivity? and 2) does downregulation of Rnf2 alter levels of ubiquitinated H2A and chromatin structure in regions of neurodevelopmentally critical genes? This project will leverage cutting-edge epigenetic techniques to provide novel insights into the mechanisms underlying Cd-mediated behavioral abnormalities.

Amyotrophic Lateral Sclerosis (ALS) is a progressive fatal disease with a median survival period of three years from symptom onset. There are no effective disease modifying therapeutics and the etiology of the disease remains largely outstanding. While some cases (<10%) are due to known genetic mutations (i.e., familial), the vast majority of cases (>90%) are referred to as sporadic ������������������ occurring at random. Thus, it has been suggested that one������������������s local environment plays a major role in the risk for ALS. In addition, recent research emphasizes the link between early-life exposures and increased risk of adult disease onset. Herein, we hypothesize that there is overlap amongst the processes that are perturbed in both genetic and sporadic cases of ALS. To probe this hypothesis, we will leverage a transgenic zebrafish line with an ALS-associated mutation in the superoxide dismutase 1 (SOD1) gene in the presence and absence of a suspected neurotoxicant, beta-methyl-amino alanine (BMAA). Deep protein sequencing and phenotypic assays will be evaluated to provide insight into the molecular pathways that contribute to the genetic and environmental mechanisms of ALS and motor neuron degeneration.

Our objective is to provide a centralized, publicly available resource with comprehensive, well-annotated data and analysis tools that informs design and interpretation of environmental health studies and promotes novel insights into the etiologies of environmentally influenced diseases. Most human diseases involve interactions between genetic and environmental factors; however, the basis of these complex interactions are not well understood and limit improvements in toxicity prediction, risk assessment, research prioritization and therapeutic interventions. We developed the Comparative Toxicogenomics Database (CTD; http://ctdbase.org) to enhance understanding about environment-disease connections by providing manually curated data describing chemical-gene/protein interactions and chemical- and gene/protein-disease relationships from the peer-reviewed literature and integrating these data with select external data sets (e.g., pathways and biological process data) and novel data analysis tools. In this application, we propose to leverage our expertise and CTD infrastructure to: 1) enhance the capacity to identify environment-disease connections by curating and integrating exposure data into CTD; and 2) expand the capacity for prediction, analysis and interpretation of environment-disease networks by developing novel analysis and visualization tools that include exposure data. This proposal responds to the needs expressed by the NIEHS and partner agencies for inclusion of exposure data when prioritizing research and performing toxicity testing, it addresses the need for centralization of exposure data in a broader biological context and it will provide ?real-world? exposure context for existing data in CTD. The resulting resource will enable new opportunities for understanding and prioritizing human health effects from exposure and their underlying etiologies and coordinate data key to enhancing the capacity for toxicity prediction and risk assessment.

The long-range goal of the proposed project is to provide a centralized, freely available resource with comprehensive, well-annotated data and analysis tools that informs hypothesis development and interpretation of environmental health studies and promotes understanding about the etiologies of environmental diseases. Most human diseases involve interactions between genetic and environmental factors. The environment is implicated in many common conditions such as asthma, cancer, and diabetes; however, the etiology of these widespread diseases remains unclear. More than 85,000 chemicals are currently used in commerce, challenging elucidation about chemical mechanisms of action and prioritization of environmental research. Integration of critical data with novel analysis approaches is required to understand environment-disease associations and is essential for improving toxicity prediction, risk assessment, regulation and development of effective therapeutic interventions. We developed the freely available Comparative Toxicogenomics Database (CTD; http://ctd.mdibl.org) to address this need. CTD provides manually curated data describing cross-species chemical-gene interactions and chemical- and gene-disease relationships from the peer-reviewed literature and integrates this information with select external data sets (e.g., molecular pathways) and novel analysis tools. In this application we propose to: 1) comprehensively curate chemical-gene-disease interactions and expand the scope of phenotype curation to include cellular and diverse organism effects that will enable users to: a) identify biomarkers of environmentally influenced diseases and b) infer potential human health consequences from toxicological studies in model organisms and in vitro studies; and 2) design and implement new tools to facilitate development, analysis and interpretation of novel hypotheses focused on chemical-gene-disease interaction networks. This proposed project will leverage our cutting-edge software development, curation expertise and well-established, flexible infrastructure to facilitate increased understanding of critical environmental health issues in direct alignment with emerging research priorities.