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European Petroleum Refiners Association (M1603310) 08/01/16 though 12/31/18

New Technologies to Underpin Category Approaches and Read-across in Regulatory Programmes (CAT-APP)

The overall objective of this project is to develop a workflow for category read-across for substances characterized as UVCB (Unknown or Variable composition, Complex reaction products and Biological materials). We use petroleum substances as a case study and develop an integrated testing strategy using experimental and computational analyses to demonstrate how UVCB testing can meet the regulatory information requirements in the EU.

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Foundation for Chemistry Research and Initiatives (M1603182) 10/01/16 though 04/30/18

Olefins Streams Biological Read-Across

This project applies a “biological read-across” principle to grouping complex substances for read across by using a case study of the low benzene naphthas and resin oils and cyclodiene dimer concentrates categories. We test the hypothesis that high-content screening and high-throughput genomic analysis using a panel of human iPSC-derived organotypic cultures (hepatocytes, cardiomyocytes, endothelial cells, macrophages, neurons, etc.) can effectively group substances in these categories for read-across.

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California EPA (Co-PI with Chiu)

Risk assessment support and training to the Office of Environmental Health Hazard Assessment (OEHHA)

This support contract aims to advance OEHHA risk assessment methods and applications through technical advice and training from Texas A&M University faculty.

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NIH (T32 ES026568) 04/16 through 03/21

Regulatory Science in Environmental Health and Toxicology

This training program aims to strengthen training and research base at Texas A&M Interdisciplinary Faculty of Toxicology program and also to provide unique focus on regulatory science, a scientific discipline consisting of the development and application of scientific methods, tools, and approaches that are used to support regulatory and other policy objectives.

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EPA (RD83580201) 06/15 through 05/19

Cardiotoxicity Adverse Outcome Pathway: Organotypic Culture Model and in vitro-to-in vivo Extrapolation for High-throughput Hazard, Dose-response and Variability Assessments

The long-term objective of the Center is to advance the regulatory decision making by establishing and validating effective, accurate and fiscally responsible means for identifying/characterizing cardiac chemical hazards.

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NIH (U24 TR001950) 09/16 through 08/18

TEX-VAL: Texas A&M Tissue Chip Validation Center

This award supports a Tissue Chip Validation Center at Texas A&M University (TEX-VAL) which conducts testing of the microphysiological systems developed by NIH grantees.  It supports the resources, personnel and infrastructure for establishing functionality, reproducibility, robustness and reliability of tissue chip models that represents a wide array of human organs.

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NIH (P42 ES027704) 04/17 through 03/22

Comprehensive Tools and Models for Addressing Exposure to Mixtures During Environmental Emergency-related Contamination Events

This Center brings together a team of scientists from biomedical, geosciences, data science and engineering disciplines to design comprehensive solutions for complex exposure- and hazard-related challenges.  Our overall theme is to characterize and manage both existing and environmental emergency-created hazardous waste sites through the development of the tools that can be used by first responders, the impacted communities, and the government bodies involved in site management and cleanup.

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NIH/NIAAA (U01AA 021908) Bataller (PI) 03/13 through 05/18

Molecular Subtypes for Targeted Therapies in Alcoholic Hepatitis: Mouse Models Core

The proposed initiative "Integrated Approaches for Identifying Molecular Targets in Alcoholic Hepatitis" (InTeam) will coordinate a multidisciplinary group composed of clinicians, physician-scientists, basic scientists and bioinformatics experts. Because mouse models for alcoholic hepatitis are lacking making it impossible to evaluate promising targets in preclinical mouse studies in a meaningful manner. For this purpose, we will integrate data obtained from molecular pathology studies in humans by using animal models.

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NIH/NIEHS (R01 ES023195) 08/13 through 07/18

Genes, Genomes, and Genotoxicity: In Vivo Epigenetic Toxicology of 1,3-butadiene

This project’s overall objective is to uncover the mechanistic linkages between the genome (e.g., DNA sequence variants), epigenome (e.g., chromatin status), and molecular initiating events (e.g., DNA damage) elicited by a genotoxic carcinogen butadiene in an in vivo mouse model. Two Specific Aims will test the hypothesis that genetic variability-associated chromatin remodeling events affect the genotoxic potential of butadiene.

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European Petroleum Refiners Association (M1603310) 08/01/16 though 12/31/18

New Technologies to Underpin Category Approaches and Read-across in Regulatory Programmes (CAT-APP)

Foundation for Chemistry Research and Initiatives (M1603182) 10/01/16 though 04/30/18

Olefins Streams Biological Read-Across

California EPA (Co-PI with Chiu)

Risk assessment support and training to the Office of Environmental Health Hazard Assessment (OEHHA)

NIH (T32 ES026568) 04/16 through 03/21

Regulatory Science in Environmental Health and Toxicology

DESCRIPTION (provided by applicant): This proposal is to establish a new T32 program in Regulatory Science in Environmental Health and Toxicology at Texas A&M University. Funds are requested to support four pre-doctoral (Ph.D. candidates) and two post-doctoral trainees in the existing highly integrated degree-granting Interdisciplinary Faculty of Toxicology program. The goal is to prepare trainees to function as independent researchers and/or practitioners in a multidisciplinary setting, by providing training in mechanistic research and risk assessment with a focus on scientifically sound, risk-based regulatory evaluations of the effects of chemicals on human health and the environment. To achieve this goal a team of 18 outstanding investigators has been assembled with specialties in Toxicology, Public Health, Risk Assessment, Exposure Science, Geochemistry, Cancer Biology, Epidemiology and Statistics. Recruitment will be conducted through traditional external advertisement, as well as from the externally funded Texas A&M research experience for undergraduates and public health and toxicology masters-level traineeship programs. Trainees will undertake two laboratory rotations in their first year in the program and follow a structured core academic curriculum that includes basic and advanced toxicology, pathology, biochemistry, statistics and research ethics, combined with courses in risk assessment and exposure assessment. In the second year, additional specialized training in either a Mechanistic Research or a Health Assessment track will be offered through elective courses that will further prepare trainees for careers in research and/or public health practice. A distinctive feature of the program is a strongly encouraged hands-on summer externship through a broad and diverse network of state and federal governmental regulatory agencies, as well as industry and non-governmental organizations. Following the first two years, trainee support for both pre- and post-doctoral fellows will shift to their mentor's or independent funding The proposed mentors have strong records of competitive support from Federal, State and other sources and this group is exceptionally well balanced with respect to expertise, gender and academic career level. Graduates from the program will be highly successful in academia, industry, governmental agencies and other professional settings and will improve public health protection through innovative and rigorous mechanistic research and risk assessment practice in support of science-based regulatory decision-making.

PUBLIC HEALTH RELEVANCE: This training program builds on a long-standing and successful history of training scientists for careers in toxicology and environmental health at Texas A&M University. We aim to strengthen training and research base and also to provide unique focus on regulatory science, a scientific discipline consisting of the development and application of scientific methods, tools, and approaches that are used to support regulatory and other policy objectives. As the fields of toxicology and environmental health acquire new tools to better detect and characterize human health hazards, our trainees will receive a strong, broad background in basic science with opportunities to specialize in research and/or decision-making for protection of public health and the environment.

EPA (RD83580201) 06/15 through 05/19

Cardiotoxicity Adverse Outcome Pathway: Organotypic Culture Model and in vitro-to-in vivo Extrapolation for High-throughput Hazard, Dose-response and Variability Assessments

DESCRIPTION (provided by applicant):  The WHO estimates that up to 23% of the global burden of cardiovascular diseases, a leading cause of death, is attributable to environmental chemicals. Methods for assessment of cardiac safety of non-pharmaceutical agents lag behind the traditional health hazards of concern to human health (carcinogenicity, mutagenicity, reproductive toxicity, etc.). The long-term objective of the Center is to advance chemical risk assessment by establishing and validating effective, accurate and fiscally responsible means for identifying/characterizing cardiac chemical hazards.

Recent advances in stem cell research and establishment of robust protocols for culturing, distribution and phenotyping holds promise for development of a functional cardiac OCM for modeling cardiovascular disease and testing for chemical hazards. The central hypotheses of this proposal are that: (i) stem cell-derived cardiomyocyte cultures constitute an effective OCM for predictive toxicity screening of environmental chemicals; (ii) a population-based experimental design utilizing a panel of human iPSCs and mouse Collaborative Cross (CC) can assess variation in toxicity to better characterize uncertainties; and (iii) integration of dosimetry with screening provides an in vivo context to in vitro data and improves human health assessments. Project 1 will conduct population-based concentration-response high-content/-throughput in vitro screening of up to 200 ToxCast chemicals in iPSC-derived cardiomyocytes from 100 humans, and will collect pharmacokinetic data using hepatocytes. Project 2 will conduct mouse population-based in vitro screening of these chemicals in CC-derived cardiomyocytes followed by in vivo validation in the CC strains. Project 3 will conduct dose-response modeling to establish appropriate point of departure, genome-wide association analyses and in vitro-to-in vivo extrapolation modeling.

NIH (U24 TR001950) 09/16 through 08/18

TEX-VAL: Texas A&M Tissue Chip Validation Center

DESCRIPTION (provided by applicant): Texas A&M Tissue Chip Validation Center This proposal is to establish a Tissue Chip Validation Center at Texas A&M University (TEX-VAL) which will conduct testing of the microphysiological systems developed by NIH grantees. Our goal is to provide resources, personnel and infrastructure for establishing functionality, reproducibility, robustness and reliability of 8-12 tissue chip models that will represent a wide array of human organ and tissue systems. To achieve this goal we have assembled a team of 7 outstanding investigators who specialize in toxicology, in vitro and in vivo testing, microscopy, genomics, pharmacokinetic modeling, bioengineering, analytical chemistry and risk assessment. These investigators will closely oversee a team of highly qualified staff members who, in collaboration with tissue chip developers, will conduct validation experiments, analyze data, generate detailed reports and ensure that the data are available to the NIH Tissue Chip Program through an accessible database. Quality management plan and quality assurance project plans will be developed and overseen by a staff member with experience in these procedures and applicable regulations. All experimental protocols and data records will adhere to the highest standards based on the existing Organization for Economic Cooperation and Development (OECD) guidance for describing non-guideline in vitro test methods, as well as appropriate guidance on validation of alternatives to animal methods from the Food and Drug Administration and the National Toxicology Program. The TEX-VAL Center will utilize Texas A&M University's existing extensive infrastructure for medium- and high-throughput in vitro screening and high-content imaging at the Institute for Biosciences and Technology (Houston, TX) and College of Veterinary Medicine and Biomedical Sciences (College Station, TX), analytical chemistry at the Geosciences and Environmental Research Group (College Station, TX), and bioengineering and microfluidics at the NanoBio Systems Laboratory (College Station, TX). TEX-VAL Center will engage with the NIH tissue chip grantees and the IQ Consortium, as well as additional experts in the pharmaceutical and chemical industry, government agencies and academia to address questions on tissue chip validation, in vitro to in vivo concordance, untargeted metabolomics analyses, selection of appropriate cell types, experimental protocols, or selection of appropriate test compounds and positive and negative controls. The laboratories and investigators involved in the TEX-VAL have decades of experience with rigor, reproducibility and replication of data through multi-disciplinary research collaborations and service contracts with industry, state and federal government, and academic collaborators. In addition, TEX-VAL has an extensive network of partnerships with regulatory agencies in the USA and Europe already in place, which will serve as an important channel for engagement with diverse stakeholders to communicate the scientific promise and technical robustness, as well as any important limitations, of the tested tissue chips.

PUBLIC HEALTH RELEVANCE: TEX-VAL is a Tissue Chip Validation Center at Texas A&M University that was established with a goal to testing a number of microphysiological systems developed by other academic investigators. Tissue chips are complex bioengineered systems that aim to re-create human organs or tissues on the chip and thus replace testing of drugs and chemicals in animals and humans. TEX-VAL will use reference chemicals to establish whether performance of tissue chips is reproducible and whether the data that can be obtained from them can be used by companies and regulatory agencies to make decisions about safety and efficacy of the chemicals.

NIH (P42 ES027704) 04/17 through 03/22

Comprehensive Tools and Models for Addressing Exposure to Mixtures During Environmental Emergency-related Contamination Events

DESCRIPTION (provided by applicant): Comprehensive tools and models for addressing exposure to mixtures during environmental emergency-related contamination events Overall Program Description Climate change and shifts in domestic economic activity markedly increase risks from catastrophic chemical contamination events resulting from weather-related or anthropogenic emergencies. The complexities of hazardous chemical exposures, potential adverse health impacts, and the need to rapidly and comprehensively evaluate the potential hazards of exposures to complex mixtures call for novel approaches in the Superfund Research Program. This Center brings together a team of scientists from biomedical, geosciences, data science and engineering disciplines to design comprehensive solutions for complex exposure- and hazard-related challenges. Our overall theme is to characterize and manage both existing and environmental emergency-created hazardous waste sites through the development of the tools that can be used by first responders, the impacted communities, and the government bodies involved in site management and cleanup. Our case study is a hurricane or flooding event that impacts Galveston Bay/Houston Ship Channel area and leads to exposure to contaminated sediments. Project 1 will study fate and transport of complex environmental contaminants in sediments and incorporate this information into environmental models. Project 2 will develop novel low-cost broad-acting sorption materials suitable for mitigation of acute exposures to complex contaminant mixtures. Projects 3 and 4 will take advantage of the discoveries in cell imaging and stem cell biology to establish predictive in vitro methods for quantitative evaluation of the complex mixture- perturbed adverse outcome pathways and intra- and inter-individual variability in toxicity. An Exposure Science Core will be developing and applying novel sensitive analytical methods for targeted and un-targeted analysis of a broad array of contaminants in environmental and biological samples. A Data Science Core will develop computational and statistical tools for analysis and integration of ?big data? in environmental health. A Decision Science Core will develop an integrated toxicokinetic, human health, and economic models to support environmental health decisions. The Center will engage with community organizations and public health practitioners in Texas to address health concerns of the populations that may be impacted by environmental emergency-related contamination events. We will train students and postdoctoral fellows in inter-disciplinary approaches across our scientific areas, decision making and emergency response. The research translation to local, state, national and international stakeholders will be conducted through technology transfer and comprehensive outreach for the solutions developed by the Center. Finally, the management of this program will be conducted in close partnership with the administration at Texas A&M University and Health Science Center, the NIEHS-funded Center for Translational Environmental Health Research, and overseen by the advisors representing academia, federal and state agencies, industry and a non-governmental organization.

PUBLIC HEALTH RELEVANCE: Overall Program Narrative This Center is focused on developing better, faster, more informative research tools and computational models that aid during response to and recovery from environmental emergencies. Climate change and human activity increase vulnerability to disasters that may involve exposure to hazardous chemicals. We bring together a team of scientists from biomedical, geosciences, data science and engineering disciplines to propose solutions for characterization and management of both existing and environmental emergency-created hazardous waste sites. The case study is a hurricane or flooding event that impacts Galveston Bay/Houston Ship Channel area and leads to exposure to contaminated sediments.

NIH/NIAAA (U01AA 021908) Bataller (PI) 03/13 through 05/18

Molecular Subtypes for Targeted Therapies in Alcoholic Hepatitis: Mouse Models Core

DESCRIPTION (provided by applicant): The development of new targeted therapies for alcoholic hepatitis (AH) is one of the more urgent needs in clinical hepatology. To reach this goal, large multidisciplinary networks are required. The proposed initiative "Integrated Approaches for Identifying Molecular Targets in Alcoholic Hepatitis" (InTeam) will coordinate a multidisciplinary group composed of clinicians, physician-scientists, basic scientists and bioinformatics experts. The overarching hypothesis of InTeam is that the most rational way to provide a useful framework for future clinical trials in (AH) consists of the (i) determination of ey drivers of the disease process, (ii) classification of molecular profiles and subtypes of AH, and (iii) identification of "druggable" targets based on both key drivers and molecular classification. Moreover, mouse models for AH are lacking making it impossible to evaluate promising targets in preclinical mouse studies in a meaningful manner. For this purpose, InTeam will integrate data obtained from molecular pathology studies in human AH and functional studies of key pathways in animal models. The proposed InTeam consortium includes three research projects, ten clinical centers, a Human Biorepository and a Mouse Models Core. The Human Biorepository Core will generate the to-date largest collection of samples from patients with AH from 10 academic liver centers and a comprehensive database that will serve as a basis for the proposed translational studies and be a valuable asset for the broader scientific community. The Mouse Models core will conduct murine studies after establishing and evaluating mouse models of AH based on the pathophysiology and molecular drivers of human AH determined by this consortium. The three scientific projects will combine a thorough molecular characterization of patients with AH with studies on key and targetable pathways that drive key aspects of AH disease progression and outcome such as inflammation, injury and regeneration. Project 1 ("Molecular Subtypes for Targeted Therapies in Alcoholic Hepatitis", PIs: Ramon Bataller and Philippe Mathurin) will identify molecular and cellular drivers of AH to provide a molecular classification using RNA sequencing, kinomic, metabolomic and novel systems biology approaches, and determine contributors to unfavorable outcome and the associated progenitor cell accumulation. Project 2 ("DAMPs for Targeting Alcoholic Hepatitis", PIs: Robert Schwabe and Wajahat Mehal) will explore the contribution of damage-associated molecular patterns (DAMPs) including HMGB1 and mitochondrial DAMPs, to the development of hepatic and systemic inflammation, and organ damage in AH. Project 3 ("Microbiota as Therapeutic Targets in Alcoholic Hepatitis", PIs: Bernd Schnabl and David Brenner) will using cutting-edge pyrosequencing and bioanalytical tools to investigate changes in the intestinal microbiome, metatranscriptome and metabolome as potential contributors and targets for therapeutic interventions in AH. In summary, the InTeam network will provide a unique combination of the to-date largest systematic sample and data collection of AH patient samples with a strong group of scientists dedicated to translational AH research and a large network of participating clinical centers. We anticipate that the systematic approach and translational nature of this consortium will advance the understanding of AH, and provide novel approaches for its prevention and treatment.
PUBLIC HEALTH RELEVANCE: Alcoholic hepatitis is a deadly form of alcoholic liver disease that needs novel targeted therapies. The development of such therapies requires the identification of the key molecular drivers of this disease. This translational research project wil study a large multicentric cohort of patients with alcoholic hepatitis using next-generation technologies in order to provide a precise molecular characterization of the patients and identify key disease drivers. By using systems biology models to integrate data obtained with RNA sequencing and kinase analysis, we will be able identify different molecular subtypes based on the prevailing disease mechanism. These results can be very useful for the designing of successful clinical trials with novel targeted therapies.

NIH/NIEHS (R01 ES023195) 08/13 through 07/18

Genes, Genomes, and Genotoxicity: In Vivo Epigenetic Toxicology of 1,3-butadiene

DESCRIPTION (provided by applicant): Epigenetic eprogramming has been proposed as an integral part of the "genome instability" enabling characteristic of cancer cells. Chemical-induced epigenetic changes may be a consequence of DNA damage, or may be part of the non-genotoxic mechanisms of carcinogenesis. Our recent studies provide critical additional insights into linkages between genotoxic and epigenetic mechanisms of carcinogenesis. First, using a multi-strain mouse model of the human population, we showed that important inter-individual (e.g., inter- strain) differences exist in both genotoxic and epigenotoxic effects of the classic genotoxic carcinogen 1, 3-butadiene and other chemicals. Second, we confirmed the hypothesis that the chromatin remodeling response is an underlying mechanism for the inter-strain differences in butadiene-induced DNA damage. These novel findings shaped this project's overall objective to uncover the mechanistic linkages between the genome (e.g., DNA sequence variants), epigenome (e.g., chromatin status), and molecular initiating events (e.g., DNA damage) elicited by a genotoxic carcinogen butadiene in an in vivo mouse model. Two Specific Aims will test the hypothesis that genetic variability-associated chromatin remodeling events affect the genotoxic potential of butadiene. In Specific Aim 1, we will extend our exciting finding that major differences in the extent of butadiene- induced DNA damage between inbred mouse strains are the result of epigenetically-controlled chromatin status. We will utilize deep sequencing-based DNaseI hypersensitivity mapping and chromatin immunoprecipitation analyses of representative histone modifications that regulate chromatin status, coupled with RNA sequencing-enabled gene expression analysis and measurements of butadiene-specific DNA damage. This data will permit deeper understanding of the toxicant-induced changes in chromatin in butadiene-sensitive and resistant strains. We will probe these events in both sexes and in target and non- target tissues for butadiene-induced carcinogenesis. In Specific Aim 2, using similar experimental techniques we will connect chromatin variation and genotoxic effects of butadiene with DNA sequence variation. To do so, we will use a large panel of recombinant inbred mouse lines from the Collaborative Cross resource, a unique and powerful tool for population genetics studies in experimental animals. In summary, this proposal not only will use the most novel tools to investigate carcinogen effects on genome biology, but it also will offer experimental proof to a paradigm-shifting concept that genetically-determined chromatin status modulates disease risk from genotoxic exposures.

PUBLIC HEALTH RELEVANCE: Environmental chemicals may cause human disease via numerous molecular pathways. Despite the complexity of the associations between exposures and adverse health outcomes, two toxicity mechanisms linked to the structure of DNA are recognized as crucial drivers in disease pathogenesis. One is the ability of chemicals to cause DNA damage and mutations, called genotoxicity, and the other is effects on DNA structure or packaging, called epigenetic events. In addition, subtle inherited variants in DNA sequence may have profound impact on the susceptibility to disease. This application aims to uncover the fundamental mechanistic linkages between the genome, epigenome, and DNA damage by an environmental and occupational carcinogen, 1, 3-butadiene. The significance of this research is in understanding the causes of human environment-associated disease, as well as in determination of genetic factors that may be responsible for individual susceptibility.