Asthma affects an estimated 300 million individuals worldwide and is the leading cause of childhood hospitalizations in the United States. The developmental or fetal origins hypothesis states that early life events, especially those occurring in utero, can markedly affect disease susceptibility. The fetal lung is comprised of both structural and immune cells. The development of the fetal lung is a complex interaction between the fetal environment and genes that are expressed at certain developmental times. The major goal of this project is to demonstrate that the structural and immune genes that are crucial to the early stages of lung development, a time in which airways branching is initiated and completed, are key regulators of a disease characterized by airways obstruction, asthma. Moreover, our goal is also to show that the genes whose expression is modified by in utero smoke exposure during early lung development will play a significantly increased role in the development of asthma. We have structured our specific aims to accomplish this goal as follows: (1) Genes crucial to the normal immune and structural development of the lung will be identified via the use of fetal lung samples and expression microarray technology. These genes will be correlated with the expression of immune CD4+ cells from asthmatics;polymorphic variants in the genes will also be tested for their association with asthma in well-established asthma cohorts. (2) Genes whose expression is significantly altered by in utero smoke exposure during early lung development will be identified by performing microarray analysis on in utero smoke exposed fetal lung samples and comparing to non-exposed samples. These genes will be correlated with the expression CD4+ asthmatic cells that have or have not been exposed to in utero or environmental tobacco smoke. Using these genes, genetic association studies focusing on asthma outcomes and the modification of these outcomes by smoke-exposure will be performed. (3) The genes identified will be validated for their effects in a murine model of asthma by way of real time PCR analysis on in utero smoke exposed and non-exposed mice. Several genes will then be studied in detail for their ability to influence a murine immune cell critical to asthma susceptibility, the T-reg cell. These findings may ultimately lead to identification of new therapeutic targets for asthma, as well as to the formation of a prognostic test for the identification of subjects susceptible to asthma. Additionally, by integrating developmental genomics with population genetics, this approach may be generalizable to other diseases affecting either the lung or other organ systems.
This project seeks to identify genetic markers most closely associated with the genetic expression signature during normal and in utero smoke-exposed lung development. By demonstrating that these markers also correlate with asthma susceptibility and outcomes, the markers may eventually be used to formulate novel therapies and preventative strategies. Since asthma remains the leading cause of childhood hospitalizations and school absences in the United States, both novel therapies and preventative strategies have the potential to substantially decrease the morbidity and financial burden related to this disease.
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