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Michael Cowley

Assoc Professor

Toxicology Building 1104M

Publications

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Grants

Date: 05/11/20 - 3/31/24
Amount: $6,709,274.00
Funding Agencies: National Institutes of Health (NIH)

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.

Date: 05/19/20 - 3/31/24
Amount: $1,359,129.00
Funding Agencies: National Institutes of Health (NIH)

Cadmium is a toxic metal that is a major public health concern, due to its ubiquity in the human environment. If successful, our work will show that exposure to cadmium during development causes non-alcoholic fatty liver disease in later life through activating a specific set of genes, identifying these genes as potential markers of disease susceptibility and novel targets for treatment. Given that NAFLD affects 30-40 % of the US adult population, and has been linked to metabolic impairments and a shorter lifespan, findings from our work have the potential to improve disease prediction and management for a large number of people.

Date: 03/25/22 - 3/31/23
Amount: $37,883.00
Funding Agencies: NCSU Center for Human Health and the Environment

Cadmium is a widespread contaminant, released into the environment through natural and anthropogenic processes. Exposure before and during pregnancy is linked to a range of negative health outcomes in children, including low birthweight, cognitive and behavioral delays, and motor skill deficiencies. Recently, we have discovered evidence for a role for Hox genes in the neurodevelopmental hazard of cadmium exposure. Newborn mice exposed to cadmium in utero have enlarged brains, increased retinoic acid signaling and unexpected Hox gene expression. Adult mice demonstrate abnormal anxiety and activity behaviors. We hypothesize that prenatal cadmium exposure perturbs retinoic acid and growth factor-mediated Hox expression, altering pattern development of the central nervous system, leading to the observed developmental health problems in children, especially in regions with higher levels of cadmium exposure in pregnant women. To investigate this hypothesis, we will first generate a high resolution map of the Hox expression axis along segments of the brain and spinal cord, along with establishing a characteristic cadmium induced retinoic acid and fibroblast growth factor and growth differentiation factor gradient. We also aim to determine the morphological and volumetric changes responsible for cadmium induced brain enlargement using magnetic resonance microscopy. Through this pilot project we will generate the preliminary data necessary to support an innovative NIEHS R01 or F32 application to study the significance of Hox genes and nervous system patterning in developmental cadmium toxicity.

Date: 09/15/17 - 2/28/22
Amount: $485,190.00
Funding Agencies: National Institute of Environmental Health Sciences (NIEHS)

The environment to which we are exposed during early life, such as toxic chemicals or stress, can influence our health as adults. The mechanisms through which early life exposures program these health effects are unclear, but understanding them will be critical for designing therapies to reverse them. This project will determine how exposure to the toxic metal cadmium during development causes health effects in later life. Cadmium is a key health concern for some communities who experience high levels of this toxic metal in the soil. This work will identify potential therapeutic targets, opening up the possibility of finding ways to counteract the toxic effects of cadmium exposure.

Date: 04/20/15 - 3/31/21
Amount: $6,127,354.00
Funding Agencies: National Institutes of Health (NIH)

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.

Date: 03/15/20 - 11/30/20
Amount: $1,058.00
Funding Agencies: National Institutes of Health (NIH)

Non-alcoholic fatty liver disease (NAFLD) affects 30 % of the US adult population, and increases the risk of hepatocellular carcinoma. NAFLD is being diagnosed at increasingly younger ages, suggestive of an early life origin for the disease. Consistent with this idea, we have shown that having a mother with metabolic syndrome - defined as a collection of inter-related physiological deficiencies including obesity, insulin resistance and hypertension - is a major risk factor for developing NAFLD in adolescence. The proposed work will build on this foundation to determine the molecular mechanisms responsible for NAFLD development in response to maternal metabolic syndrome. We will combine mouse and cell culture models to test the specific hypothesis that a set of genes called imprinted genes play a central role in this process. Our results will identify novel pathways that promote NAFLD and will identify potential targets for new therapies to reverse NAFLD progression.

Date: 12/01/19 - 11/30/20
Amount: $30,791.00
Funding Agencies: National Institutes of Health (NIH)

Non-alcoholic fatty liver disease (NAFLD) affects 30 % of the US adult population, and increases the risk of hepatocellular carcinoma. NAFLD is being diagnosed at increasingly younger ages, suggestive of an early life origin for the disease. Consistent with this idea, we have shown that having a mother with metabolic syndrome - defined as a collection of inter-related physiological deficiencies including obesity, insulin resistance and hypertension - is a major risk factor for developing NAFLD in adolescence. The proposed work will build on this foundation to determine the molecular mechanisms responsible for NAFLD development in response to maternal metabolic syndrome. We will combine mouse and cell culture models to test the specific hypothesis that a set of genes called imprinted genes play a central role in this process. Our results will identify novel pathways that promote NAFLD and will identify potential targets for new therapies to reverse NAFLD progression.

Date: 06/01/18 - 3/31/19
Amount: $37,305.00
Funding Agencies: NCSU Center for Human Health and the Environment

Non-alcoholic fatty liver disease (NAFLD) affects 29 million people in the US and is associated with obesity and type 2 diabetes, two major public health challenges. Susceptibility to NAFLD can be programmed during development by environmental factors, including a maternal high fat diet. However the molecular mechanisms responsible for this effect remain elusive. To study these mechanisms, we established a mouse model of maternal high fat diet which enables us to distinguish between the effects of prenatal and postnatal exposure. One of our most striking findings is that postnatal, but not prenatal, exposure is associated with hepatic steatosis at weaning. Using a combination of global and targeted approaches, we showed that postnatal, but not prenatal, exposure to maternal high fat diet is associated with up-regulation of a network of imprinted genes in the liver (the Imprinted Gene Network, IGN) controlled by the transcription factor Zac1. By over-expressing Zac1 in cultured hepatocytes, we show that activation of the IGN promotes lipogenic and fibrotic pathways, arguing for a role for the IGN in contributing to NAFLD progression in response to maternal high fat diet. In this proposal, we build on these preliminary findings to functionally characterize the cell autonomous role of the IGN in hepatocytes, and to test the hypothesis that the elevated expression of the IGN is caused by inappropriate epigenetic regulation, thereby identifying a mechanistic bridge between environmental exposure and altered genome function. Data collected will provide the foundation for an NIEHS R01 application in 2019.

Date: 07/01/16 - 6/30/17
Amount: $37,875.00
Funding Agencies: NCSU Center for Human Health and the Environment

Mesenchymal stem cells (MSCs) are multipotent stem cells that retain the ability for “self-renewal” and/or differentiate into a variety of mesenchymal lineages, including osteoblasts (bone cells), chondrocytes (cartilage cells), and adipocytes (fat cells). Both self-renewal and differentiation of MSCs are governed through strict cross talk between epigenetic modulators that regulate chromatin conformation and transcriptional regulators that mediate gene transcription. Recently, a theme that is emerging suggests that exogenous exposures to environmental agents may perturb regulatory networks that coordinate the balance of MSC commitment towards defined mesenchymal lineages. In this context our group has demonstrated that activation of the aryl hydrocarbon receptor (AhR) imparts a repressive effect on both osteogeneic and adipogeneic MSC differentiation. In this study we seek to generate a targeted genomic map of quantified transcriptional and epigenetic modifications associated with AhR mediated repression of mesenchymal stem cell differentiation in two sub aims that: 1) identify transcriptional alterations in MSC differentiation networks; and 2) define the underlying epigenetic mechanisms responsible for altered transcription. Exposures to compounds that alter stem cell differentiation may represent an environmental link to current diseases of concern including obesity and osteoporosis. The ability of exogenous agents to modify epigenetic pathways that regulate fetal programing may have profound developmental consequences that can manifest early in development or impact onset and progression of adult diseases. We propose that studies presented below will provide a broader conceptual understanding of putative mechanisms driving adverse outcomes in mesenchymal stem cells and help inform human heath risk.

Date: 09/01/15 - 8/31/16
Amount: $37,852.00
Funding Agencies: NCSU Center for Human Health and the Environment

Endocrine disrupting compounds (EDCs) are natural or synthetic chemicals that interfere with endocrine signaling. Exposure to EDCs during development is associated with disease in adulthood, including obesity and behavioral disorders, suggesting that exposure in early life can program molecular changes that are maintained through cell divisions. Epigenetic modifications to DNA, which influence how genetic information is interpreted by the cellular machinery, are strong candidates for linking developmental exposures to adult health, because they can be perturbed by environmental stressors and propagated through mitosis. EDCs can influence epigenetics, but little is known about the mechanisms through which this occurs, and how these changes affect mRNA production and protein abundance. Establishing this is critical for understanding how EDCs can lead to a disease state. Using embryonic stem cells with a unique genetic background, we will develop and test a model of early developmental exposure to EDCs, which will provide detailed mechanistic insights into their modes of action. We will use imprinted genes as tools for determining the effects of exposure. Imprinted genes exist in two epigenetic states in the same nucleus, meaning that we can examine exactly how EDCs induce epigenetic changes independent of DNA sequence. This pilot project will demonstrate the utility of the model for studying the mechanistic relationships between EDC exposure, the epigenome, the transcriptome and the proteome. In addition to fostering an interdisciplinary collaboration between two junior CHHE investigators, the data generated will provide a foundation for an NIEHS R01 application.


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