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David Aylor

Assoc Professor

Thomas Hall 3570A

Bio

We study how genetic variation controls complex traits, susceptibility to disease, and individual molecular biology. Most prevalent human diseases, most agriculturally important traits, and evolutionary fitness are complex traits, which means they are influenced by a combination of multiple genetic and environmental factors. A long-standing goal in the field is to identify quantitative trait loci (QTL) – genetic variants that influence complex traits. Discovering these relationships is challenging because the individual factors each have small effects, and because genetic variants often interact with the environment (GxE) or other genes (epistasis). Figuring out how these variants change the function of cells or molecules has been even more difficult. Understanding these genetic mechanisms will enable the translation of model organism research to humans and uncover new principles of genetics and genome science. We develop and apply systems genetics approaches that enable us to discover QTL and reveal their mechanisms.

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: 01/25/22 - 1/24/24
Amount: $10,000.00
Funding Agencies: Jackson Laboratory

Obesity is a global public health crisis. Complementary strategies such a pharmaceuticals and dietary interventions are needed to combat this epidemic. Green tea (GT) is rich in flavonoids, including (−)-epigallocatechin gallate (EGCG). Questions remain regarding translation of anti-obesity activities of EGCG (and all phytochemicals) to humans. Lack of genetic diversity in preclinical models has been proposed as a source of poor translational success, but little research has been done to test this hypothesis. Genetic diversity models, including Outbred (DO) cohorts, may provide data that will improve translational success of phytochemicals. The overall objective of this proposal is to utilize DO mice to develop preliminary “proof-of-concept” data regarding the impact of background genetics on the anti-obesity activities of EGCG. Our central hypothesis is that DO mice with will exhibit significant variability in the anti-obesity activities of EGCG. In the present study, we aim to estimate the following in a DO cohort1) variability in anti-obesity activities of EGCG across diverse genetic backgrounds and 2) narrow-sense heritability of responsiveness/sensitivity to EGCG. The proposed work is innovative, as few studies have used CC or DO mouse cohorts to inform precision nutrition using phytochemicals. The rationale for the proposed work is that achievement of our aims will significantly enhance our understanding of the translatability of EGCG to combat obesity in humans. Our study has the potential to demonstrate whether EGCG has broadly translatable anti-obesity potential, or requires highly personalized implementation based on genetics. These data will inform larger studies that map QTL to identify genetic loci or genes associated with responsiveness/sensitivity to EGCG, which may reveal previously unknown mechanism and targets for EGCG activities, and suggest strategies for precision implementation in humans. These insights will likely facilitate improved translatability and efficacy of EGCG for mitigation of obesity in humans.

Date: 12/01/19 - 11/30/23
Amount: $115,407.00
Funding Agencies: National Institutes of Health (NIH)

To accommodate the budget, Dr. Aylor has reduced his participation in the 2019-2020 budget period to 0.60 summer month's effort (5%). Dr Aylor has replaced the graduate student with a Postdoctoral scholar who will have 3 calendar months of effort (25%) on the project. The Postdoc will have the bioinformatics expertise required to complete all aspects of genetic and genomic analyses described in the original statement of work. Dr. Aylor is responsible for mentoring and career development of the postdoc. The postdoc will travel to conferences to engage with complex trait genetics and mouse genomics communities, and we have allocated a portion of the budget to enable this travel. Original SOW This research project will use a cutting-edge population-based mouse resource to identify genetic variants associated with infarction. The Collaborative Cross (CC) mice harbor an abundance of genetic and diversity and preliminary results show substantial variation in infarct-related phenotypes. Dr. Aylor will collaborate with Dr. Marchuk and Dr. o on the overall study. Mr. Konneker will work under the supervision of Dr. Aylor on specific analyses described. The scope of the work to be performed at NC State includes: 1. Assist in study design using Collaborative Cross mice 2. Quantitative trait locus mapping. Pipelines for QTL mapping in the CC are already established in our lab. 3. Analysis of next-generation sequencing (NGS) data including RNA-deq. NGS data in the CC requires specific pipelines for aligning reads to highly diverse genomes. These pipelines are already established in our lab. 4. Genome analysis and bioinformatics to interrogate candidate genes. 5. Co-authoring manuscripts or sections of manuscripts relevant to the above analyses.

Date: 09/23/22 - 8/31/23
Amount: $228,000.00
Funding Agencies: National Institutes of Health (NIH)

The goal of this project is to identify genes that cause male infertility in hybrid mice. We have already established the fertility of specific hybrids. In this project, we will map the genes responsible using an outcross design. In addition, we will use single-cell genomics to understand in which cell type and at what stage of spermatogenesis these genetic variants are causing infertility. Identifying these genes will help us better understand the genetics of spermatogenesis and will help advance our understanding of infertility in men.

Date: 06/01/16 - 4/30/22
Amount: $2,910,820.00
Funding Agencies: National Institutes of Health (NIH)

Endocrine disrupting chemicals (EDCs) interfere with mammalian hormones, and can cause myriad adverse health effects, including developmental effects, neurological effects, reproductive effects, and cancer. One way that EDCs cause disease is by causing epigenomic modifications that change how genes are regulated in specific cells and tissues. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD, or dioxin) is an EDC that affects multiple tissue systems and has adverse neurodevelopmental effects. The project’s objective is to understand how TCDD exposure alters epigenomic profiles in the brain. It is often not feasible to sample brain tissue in humans, but other tissues like blood and skin can be readily sampled. This raises the question of whether epigenomic profiles associated with TCDD exposure in blood and skin are good surrogates for exposure in brain. The proposed research will test this directly using mice and mouse cells. Mice will be exposed to TCDD during adolescence, a critical time for brain development. Three specific brain regions (cortex, hypothalamus, and hippocampus), peripheral blood leukocytes, and skin will be sampled from exposed and unexposed mice. Comparing these samples will reveal robust epigenomic signatures of TCDD exposure. Importantly, the study will use the genetically diverse mouse Collaborative Cross reference population to better reflect human populations. Some individuals may be more susceptible to TCDD exposure than others, and this experimental design will capture that variation. In parallel, mouse primary cells will be exposed to TCDD in vitro to determine if cell-based systems can accurately reflect the epigenomic modifications seen in tissues. If so, cell-based systems will have many applications for research and for screening potentially hazardous chemicals. The results will be integrated with available public data sources to better understand how mouse epigenomic profiles can be used to predict TCDD effects in humans, and in additional affected tissues in mouse and humans.

Date: 12/15/20 - 3/31/22
Amount: $37,016.00
Funding Agencies: NCSU Center for Human Health and the Environment

Tetrachlorodibenzo-p-dioxin (TCDD) is a pervasive environmental contaminant that has been associated with a wide range of adverse health outcomes including liver damage, impaired immune function, and cancer of several organs. TCDD exposure induces a well-studied xenobiotic metabolism pathway that is downstream of the Aryl Hydrocarbon receptor, AhR. However, the molecular signatures of TCDD exposure last long after the acute response has subsided. We detected hundreds of differently expressed genes (DEGs) and differentially accessible chromatin regions (DARs) in mice several months after TCDD exposure had ceased, and these profiles had almost no overlap with the xenobiotic metabolism pathways. The goal of the proposed research is to understand how the global epigenome is remodeled during the period after the acute TCDD response subsides. We propose that the gene Tip30 is an essential part of the long-term response. Tip30 is upregulated during the acute response, but unlike most other genes remains upregulated for months afterwards. Likewise, accessible chromatin in a Tip30 intron was the most stable epigenetic modification that we associated with TCDD exposure, and it was found in exposed mice of both sexes throughout life up to 8 months after exposure. Separately, Tip30 has been identified as a tumor suppressor gene that has a protective role in human hepatocellular carcinomas. Our proposed research will elucidate the mechanisms of Tip30 upregulation and its effect on the global epigenome using molecular biology techniques, epigenomics, and a knockout mouse model.

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: 09/30/18 - 9/29/20
Amount: $24,956.00
Funding Agencies: National Institute for Occupational Safety & Health

The goal of this developmental research project is to demonstrate the relative sensitization potential of environmental diisocyanates in a mouse population-based model. Diisocyanates are major components of industrial paints and coatings and occupational exposures have been linked to allergenicity and asthma. Dr. Aylor will collaborate with Dr. Nylander-French, Dr. French, and Dr. Kelada on the overall study. Dr. Nylander-French will be the principal investigator on the study. The scope of the work to be performed at NC State includes: 1. Study design for Collaborative Cross mice and power analysis 2. Statistical analysis of genetic (strain) effects, treatment effects, and gene by environment interactions 3. Analysis of next-generation sequencing (NGS) data such as RNA-seq. NGS data in the CC requires specific pipelines for aligning reads to highly diverse genomes 4. Genome analysis and bioinformatics to interrogate candidate genes 5. Co-authoring manuscripts or sections of manuscripts relevant to the above analyses

Date: 12/01/18 - 11/30/19
Amount: $38,469.00
Funding Agencies: National Institutes of Health (NIH)

This research project will use a cutting-edge population-based mouse resource to identify genetic variants associated with infarction. the Collaborative Cross (CC) mice harbor an abundance of genetic and diversity and preliminary results show substantial variation in infarct-related phenotypes. Dr. Aylor will collaborate with Dr. Marchuk and Dr. Lo on the overall study. Mr. Konneker will work under the supervision of Dr. Aylor on specific analyses described. The scope of the work to be performed at NC State includes: 1. Assist in study design using Collaborative Cross mice. 2. Quantitative trait locus mapping. Pipelines for QTL mapping in the CC are already established in our lab. 3. Analysis of next-generation sequencing (NGS) data including RNA-deq. NGA data in the CC requires specific pipelines for aligning reads to highly diverse genomes. These pipelines are already established in our lab. 4. Genome analysis and bioinformatics to interrogate candidate genes. 5. Co-authoring manuscripts or sections of manuscripts relevant to the above analyses.

Date: 12/01/17 - 11/30/18
Amount: $38,469.00
Funding Agencies: National Institutes of Health (NIH)

This research project will use a cutting-edge population-based mouse resource to identify genetic variants associated with infarction. The Collaborative Cross (CC) mice harbor an abundance of genetic and diversity and preliminary results show substantial variation in infarct-related phenotypes. Dr. Aylor will collaborate with Dr. Marchuk and Dr. Lo on the overall study. Mr. Konneker will work under the supervision of Dr. Aylor on specific analyses described.


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