David Reif
Ricks Hall 344
dmreif@ncsu.edu
http://reif-lab.org
The overarching goal of research in the Reif Lab is to understand the complex interactions between human health and the environment. To accomplish this goal, we focus on developing bioinformatical/statistical methods, visual analytics, experimental design, and software for the integrated analysis of high-dimensional, multi-scale data from diverse sources.
Concurrent Evaluation of Mortality and Behavioral Responses: A Fast and Efficient Testing Approach for High-Throughput Chemical Hazard Identification , Frontiers in Toxicology (2021)
Development of a Pandemic Awareness STEM Outreach Curriculum: Utilizing a Computational Thinking Taxonomy Framework , EDUCATION SCIENCES (2021)
Extending the lymphoblastoid cell line model for drug combination pharmacogenomics , PHARMACOGENOMICS (2021)
High-throughput screening and genome-wide analyses of 44 anticancer drugs in the 1000 Genomes cell lines reveals an association of the NQO1 gene with the response of multiple anticancer drugs , PLOS Genetics (2021)
Leveraging high-throughput screening data, deep neural networks, and conditional generative adversarial networks to advance predictive toxicology , PLOS COMPUTATIONAL BIOLOGY (2021)
Multiomic Big Data Analysis Challenges: Increasing Confidence in the Interpretation of Artificial Intelligence Assessments , ANALYTICAL CHEMISTRY (2021)
The COVID-19 Pandemic Vulnerability Index (PVI) Dashboard: Monitoring County-Level Vulnerability Using Visualization, Statistical Modeling, and Machine Learning , ENVIRONMENTAL HEALTH PERSPECTIVES (2021)
ToxPi*GIS Toolkit: Creating, viewing, and sharing integrative visualizations for geospatial data using ArcGIS , (2021)
Uncovering Evidence for Endocrine-Disrupting Chemicals That Elicit Differential Susceptibility through Gene-Environment Interactions , TOXICS (2021)
Utilizing Pine Needles to Temporally and Spatially Profile Per- and Polyfluoroalkyl Substances , (2021)
Genetic Etiology of Cancer Drug Response
Funding Agencies: National Institutes of Health (NIH)
Important progress continues to be made in the treatment of most common cancers, but therapeutic benefit remains difficult to predict and severe or fatal adverse events occur frequently. The Human Genome Project has fueled the notion that genetic information can produce effective and cost-efficient selection of therapies for individual patients, but validated genetic signatures that predict response to most chemotherapy regimens remain to be identified. Numerous genes potentially influence drug response, but current candidate-gene approaches are limited by the requirement of a priori knowledge about the genes involved and the moderate size of most clinical trials often limits the power of in vitro genome wide association studies (GWAS) for cancer pharmacogenomics discovery. In response to these limitations, we have undertaken a thorough, pharmacogenomic assessment of cytotoxic effect of the majority of FDA approved anti-cancer compounds using an ex vivo model system to determine the heritability of drug-induced cell killing to prioritize drugs for pharmacogenomic mapping. These results are an important first step, and while high heritability of a trait does not guarantee successful association mapping results, it represents an important first step and the results will be used to prioritize drugs with high heritabilities for genome-wide association mapping. In the current proposal, GWAS mapping of cytotoxic agents will be performed in a European American population, and then replication GWAS mapping will be performed in an East Asian population. In addition to discovering and validating genetic variants that predict drug response, the wealth of data collected will be used to dissect the underlying etiology of drug response traits, including assessing the relative contribution of genetic, environmental, and interaction components of variation. These results will provide crucial insight to prioritize genetic variants for follow-up in precious clinical population resources, and potentially reveal new insight into the overall etiology of drug responses.
The TAMU Superfund Research Program
Funding Agencies: National Institute of Environmental Health Sciences (NIEHS)
The Texas A&M University Superfund Research 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. This partnership was formed around a common goal: to develop, apply, and translate a comprehensive set of tools and models that will aid in addressing human health consequences of exposure to mixtures during environmental emergency-related contamination events. Dr. Wright is the lead PI for a subcontract from TAMU, and will act as co-investigator to the Data Sciences Core.
Multidimensional in vivo Assessments of Engineered Nanomaterials and Biological Interactions
The overall goal of this research proposal is to gain a molecular understanding of the interactions between engineered nanomaterials (ENM) and the embryonic zebrafish. To advance our understanding and keep pace with new innovations, we increasingly need advances in ENM synthesis, biological screens and sustainability metrics. Due to the complex nature of their interactions, these areas must be addressed in the context of a highly interactive multi-disciplinary team. We propose to achieve the following research objectives: 1. Obtain multifunction ENMs with precisely defined structures to address key questions regarding how molecular level structure influences toxicity. 2. Advance the comprehensive, rapid, multi-dimensional in vivo screening approaches needed to inform design guidelines to reduce the adverse impacts associated with ENMs. 3. Collaborate with other U01 consortia investigators to develop principles that may be used to design new nanoparticles with reduced environmental impacts. We will initially collaborate with the Nanomaterials Health Implications Research (NHIR): Engineered Nanomaterials Resource and Coordination Core (ERCC). We expect that this core will provide precision-engineered, multifunction ENMs to probe the roles of surface chemistry and core characteristics in function and properties. We will rapidly evaluate bioimpacts of the reference materials using a multi-dimensional, high throughput embryonic zebrafish bioassay that we have pioneered
Graduate Training in Bioinformatics
The graduate training program in Bioinformatics at North Carolina State University requests support for 10 pre-doctoral trainees and 2 post-doctoral trainees. These trainees work at the interface of genomic science, computer science and statistics.
Cardiotoxicity Adverse Outcome Pathway: Organotypic Culture Model and In Vitro/ In Vivo Extrapolation for High-Throughput Hazard, Dose-Response and Variability Assessments
Funding Agencies: US Environmental Protection Agency (EPA)
The central hypotheses of this proposal are that: (i) stem cell-derived cardiomyocyte cultures constitute an effective organotypic culture model 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 collect pharmacokinetic data using hepatocytes. Project 2 will conduct mouse population-based in vitro screening of these chemicals in CC ESC-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.
Systematic Evaluation of the Toxicity of Per and Polyfluoroalkyl Substances
Background: The chemicals are diverse. They contain a lot of fluorine molecules. Elemental substitutions can change their properties. Different structural moieties (carbolic acid, sulfonic acid, ethers, etc.) change their properties and influence where they go in the environment, whether and how organisms take them in, how they distribute within the organism, and how they influence various biological targets. Objective: Conduct the largest comprehensive in vivo, structure-activity based toxicity studies of per- and polyfluoroalkyl substances (PFAs) and understand the partitioning of PFAs. Experimental approach: We will procure and build the largest PFA library and expose embryonic zebrafish to all PFAs in a wide range of concentrations to investigate toxicity. For each concentration of each chemical, the body burden of PFAs in zebrafish embryos as a function of time (1, 2 and 5 days) to determine its ability to enter the embryo, prior to metabolism and after an active metabolism has been established. The ability of PFAs to enter the embryo maybe impacted based on whether they will stay in the water, or stick on various surfaces. To account for this, we propose to conduct studies to determine the partitioning of the chemical structure for a subset of the PFAs at various concentrations and model the behavior of the chemical in water. The data collected in the zebrafish model will prioritize PFAs to be the most toxic and assessed in mice during early developmental stage and measure adaptive and innate immune responses as well as splenic and thymic immunophenotype. Organ samples will be taken from mice exposed to various PFAs and the concentration of PFAs will be measured. The measurements will be used to build a pharmacokinetic model that explains and predicts concentrations of PFAs in various organs of mice as a function of exposure dose. In parallel, adult zebrafish will be exposed to PFAs through dietary ingestion and the concentration of PFAs in various organs and the water will be measured over time. This data will help build a pharmacokinetic model. Expected outcome: The toxicity results from the embryonic zebrafish and mice, and the pharmacokinetic models will help EPA prioritize chemicals for further testing and may also alert chemical manufacturers that some of their commercial products may be toxic. The proposed work will help establish a knowledge base that can help predict chemical toxicity without in vivo testing.
Center for Human Health and the Environment (CHHE)
The vision of the Center for Human Health and the Environment (CHHE) is to become a global leader in environmental health sciences (EHS) along the continuum from genes to populations by building on NC State's unique research strengths and resources in quantitative biology, -omics and analytical technologies, and diverse model organisms, as well as its emerging strength in human population science. Through the purposeful interfacing of different disciplines and a systems biology framework integrating all levels of biological organization - biomolecule, pathway, cell, tissue, organ, model organism, human, and human population - CHHE will elucidate fundamental mechanisms through which environmental stressors interface with pathways, the genome, and epigenome to influence human health outcomes. CHHE has made outstanding progress in the first funding cycle. CHHE has significantly: (1) advanced innovative multi-disciplinary EHS team research; (2) expanded its NIEHS grant base; (3) increased EHS capacity at its partner institutions, East Carolina University and North Carolina Central University; (4) cultivated the next generation of EHS leaders; and (5) developed multi-directional engagement with communities affected by exposure to toxic metals and per- and polyfluoroalkyl substances. During our first funding cycle, four Research Interest Groups (RIGs) evolved organically and the Emerging Contaminants, Environmental Epigenetics and Genetics, Pulmonary Health, and Behavior and Neuroscience RIGs now represent CHHE thematic areas. In the coming cycle, we have enhanced our three facility cores to increase the impact and the basic science and translational capacity of our membership. The Systems Technologies Core provides cutting-edge technologies involving genomics, metabolomics, metallomics, and proteomics. The Comparative Pathology Core provides pathologic phenotypic assessment of the many model organisms used by members and imaging support with links back to omics technologies. The Integrative Health Science Facility Core facilitates bidirectional translation between basic science and public health outcomes by providing data science analysis and visualization support for analysis of human population and multi-omic studies as well as population-based study expertise. As a land-grant university, NC State has a dedicated community engagement philosophy that augments CHHE's Community Engagement Core and fosters relationships between CHHE and affected communities in NC which leads to collaborative interaction among researchers, educators, and citizens to enhance EHS knowledge, literacy, and health. A strong Career Development Program for early- and mid-career investigators is coordinated with a robust Pilot Project Program that supports collaborative and multidisciplinary EHS projects to enhance the research success of our members. Our CHHE mission is to continue to evolve as a premier NIEHS EHS Core Center and serve as the nexus of EHS research at NC State by providing focus, resources, and leadership for interdisciplinary research that will improve human health locally, nationally, and globally.
Investigating the Impact of Environmental Greenspace Exposure on Telomere Length
Funding Agencies: NCSU Center for Human Health and the Environment
Our proposed project will seek to explore the relationship between greenspace exposure and telomere length in a large sample from the United States. This result can provide evidence for a biological pathway that greenspace exposure influences human health. The project will also examine the spatial scale of the exposure relationship to determine the feasibility of Zip codes as an analysis unit versus census geographies and residential location. If Zip codes provide sufficient results, this spatial information would provide a means of data collection in future studies that protects participant privacy. The proposed project will expand CHHE collaborations with new connections between Drs. Hipp and Reif. Importantly, pilot funding will also provide Dr. Ogletree, postdoctoral scholar in Parks, Recreation, and Tourism Management and the Center for Geospatial Analytics, with valuable experience to establish himself in the field of environmental health research and with NHANES data, expanding the potential for a K award.
Center for Environmental and Health Effects of PFAS
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.
Gene-Environment Interactions Causing Differential Susceptibility to Chemical Exposure in High-Throughput Screening
Exposure to environmental chemicals has been linked to increases in cancer incidence, birth defects, impaired cognitive development, and neurodegenerative disease. Unfortunately, the gap between the ever-expanding number of chemicals in the environment and data on their potential health hazards continues to widen. Although recent advancements that use in vitro, high-throughput screening (HTS) technologies may speed the pace of chemical testing, those platforms cannot detect adverse health effects diagnosable only at a systemic level, such as abnormal development or aberrant behavior. Additionally, an in vivo context is needed to quantify the contribution of interindividual genetic variation to susceptibility differences in developmental or behavioral consequences of exposure. There is strong evidence that gene-environment interactions (GxE) related to individual genetic variation play an important role in health outcomes, and that these interactions are likely a major source of the heterogeneity in response to chemical exposure. Thus, understanding the role of GxE in differential susceptibility to chemical exposure will be key to protecting public health. We propose development of a collaborative bioinformatic + experimental system to study health outcomes affected by gene-environment interactions (Y=GxE) that comprehensively describes (Y), refines characterization of (E), then investigates and probes (G). This system will leverage massive data generated by HTS of chemicals through morphological and behavioral assays in embryonic zebrafish during the critical period (the first 5 days immediately after fertilization) when developmental processes are most highly-conserved between this vertebrate model organism and humans. These data will be analyzed to quantify GxE that elicit differential health outcomes following chemical exposure. The lasting significance of this proposal will be a scalable, efficient system to rapidly address questions of differential genetic susceptibility to an expanding chemical universe.
Expertise: Visualization