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Tomlinson Laboratory

Summary:

This lab has several research projects ongoing in the laboratory with the common theme of using high-throughput genomics approaches to study gene/environment interactions in development and disease

First, this lab studies the role of the aryl hydrocarbon receptor (AHR) in adult-onset cardiovascular disease (CVD). These studies are a test of the Barker hypothesis, which originated from epidemiological studies to explain the correlation between low birth rate and CVD, diabetes, obesity, and other adult onset diseases. The concept of the Barker hypothesis has been expanded to include in utero insults such as exposure to environmental agents that might influence developmental programs that adversely affect the fetus. The expanded Barker hypothesis, simply stated, is that an in utero stress; be it nutritional, chemical (drug or toxicant exposure), or physical; increases the likelihood that children borne of that mother will develop adult onset diseases and that this enhanced risk of disease is passed on to subsequent generations.

Using a mouse model system, they are testing the hypothesis that an in utero exposure of a toxicant to the fetus alters global AHR-regulated gene expression and genome-wide methylation patterns to reprogram the developing CV system resulting in heritable, trans-generational adult-onset cardiovascular disease. Thus, the primary objective of our work is to (1) correlate genome-wide methylation and global RNA expression profiles to identify those genes, signaling pathways, and developmental programs affected by a toxicant exposure during development that leads to an adult disease, and (2) determine whether the epigenetic changes in the developmental programs are inherited.

A second project in the lab is to develop new genomics technologies to examine all levels of gene expression (Fig. 3). The project involves the study of the global expression of RNA at the levels of transcription, the roles of DNA methylation in gene expression, the rates of nuclear and cytoplasmic RNA turnover, the accurate measurement of steady-state mRNA levels, and the regulation of polysome entry.

A third project in our laboratory is to determine the role of the AHR in mediating the effects of curcumin (and arsenic) on cystic fibrosis. Approximately 3,500 babies are born with CF annually, which dooms them to a drastically impaired lifestyle and reduced lifespan. Both curcumin (Fig. 4) and arsenic are ligands for the AHR. We culture human bronchial airway epithelia isolated from a ΔF508CFTR-/- patient (CFBE) and isogenic cells (CFBE+wtCFTR) complemented with the wild type cystic fibrosis transmembrane conductance regulator (CFTR). The CFBE and CFBE+wtCFTR cells are manipulated by siRNA methods such that the Ahr gene is expressed at either relatively high or low levels. A distinct advantage of using this strategy is that by virtue of the integral role the AHR plays in response to environmental agents, any corresponding differences observed in the inflammatory response and in gene expression and regulation profiles are due to the differing capacities of the AHR response. Thus, these studies are a superb means to study gene (Ahr) / environment (As or curcumin) interactions and their roles in lung inflammation.

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Last updated: 2013-07-29T14:34:01.372-04:00

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The eagle-i Consortium is supported by NIH Grant #5U24RR029825-02 / Copyright 2016