Asthma is a leading cause of childhood morbidity and normal lung function development is essential for respiratory health during childhood and subsequent adult life. We have developed preliminary data that highlight the adverse effects of prenatal tobacco smoke (PTS) exposure. PTS exposure can permanently alter the developing lung and fetal immune function, increasing risk for respiratory disease, and understanding the mechanisms of these effects may shed light on the effects of other environmental exposures. Scientists have clearly demonstrated both early-life environmental and genetic factors contribute to the pathogenesis of asthma and lung function. Recent studies highlight the importance of genetic variants and epigenetic alterations underlying environmentally-related immune function and respiratory health. We present preliminary studies showing the potential importance of genetic and epigenetic variation in the TAM (TYRO3, AXL, and MER) family of Type I receptor tyrosine kinases in early life lung function and asthma pathogenesis in the context of PTS. To provide a conceptual framework useful for addressing this critical knowledge gap, we propose an integrated epigenetic-genetic analysis of the TAM (TYRO3, AXL, and MER) family of Type I receptor tyrosine kinases to better understand the biological mechanisms underlying the impaired lung function development and increased risk of asthma associated with PTS. Specifically, this application builds on the PI's K01 project to further evaluate 1500 subjects in the Children's Health Study (CHS), a longitudinal study of air pollutant and respiratory health in 16 Southern California communities. The study will leverage an existing comprehensive resource that includes genome-wide association data, linked birth records, and extensive respiratory assessments. The project focuses on the TAM gene family for the proposed integrated analysis because these genes are important in the development of chronic inflammatory and autoimmune diseases and our preliminary data suggest epigenetic mechanisms may play a role. The proposal will accomplish the following aims: (1) characterize the association between PTS exposure and TAM gene DNA methylation and validate observed associations;(2) explore whether haplotypes are associated with TAM gene DNA methylation or modify the PTS-associated DNA methylation;(3) characterize the association between PTS exposure and promoter DNA methylation of mi-R34a and miR-199a/b levels, three miRNAs known to regulate AXL expression, and further relate to their expression levels;and (4) build a comprehensive picture of the inter- relationships between PTS exposure, CpG methylation, gene or miRNA expression, and haplotypes in the TAM genes in association with asthma and lung function using methods based on canonical correlation. The proposed integrated epigenetic-genetic analysis coupled with the novel use of newborn bloodspots (NBS) to measure prenatal exposure and epigenetic alterations is expected to offer a powerful approach to studying the epigenetic-genetic mechanism for various complex human diseases with early-life environmental origins.]

Public Health Relevance

Although our understanding of how early-life environments and genetic factors interact to affect children's respiratory health has improved in recent years, little is known about the comprehensive picture of how epigenetic state, genetic sequence, and miRNA expression interplay with each other to determine the risk of respiratory disease associated with prenatal environmental exposures. We have developed preliminary data that highlights the potential importance of the TAM (TYRO3, AXL, and MER) family of Type I receptor tyrosine kinases in early life lung function and asthma pathogenesis. The proposed research will increase the understanding of the biological mechanisms underlying impaired lung function development and increased risk of asthma associated with tobacco smoke exposure during pregnancy (PTS). Because PTS can be reduced and because epigenetics present a new array of potential therapeutic targets for intervention, the potential public health impact is larg. As these genes are important in the development of chronic inflammatory and autoimmune diseases, understanding how epigenetic and genetic profiles interact with the environment may have wider applicability to inflammatory conditions. The approach developed in this proposal will provide a conceptual framework useful for an integrated environmental epigenetic-genetic analysis of other exposures, genes and diseases.]

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
1R01ES022216-01A1
Application #
8576150
Study Section
Infectious Diseases, Reproductive Health, Asthma and Pulmonary Conditions Study Section (IRAP)
Program Officer
Mcallister, Kimberly A
Project Start
2013-09-01
Project End
2017-06-30
Budget Start
2013-09-01
Budget End
2014-06-30
Support Year
1
Fiscal Year
2013
Total Cost
$643,423
Indirect Cost
$246,988
Name
University of Southern California
Department
Public Health & Prev Medicine
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089