In agriculture industries, organic dust exposures trigger harmful airway inflammation, and individuals employed in concentrated animal feeding operations experience work-related inflammatory lung diseases, including chronic bronchitis and obstructive airway diseases. Existing therapeutics do not adequately treat the resulting airway disease. Thus, novel preventative or treatment schemes are vitally needed to combat the deleterious inflammatory effects of these exposures. The health benefits of diets high in omega-3 fatty acids (?-3 FA) are well recognized but incompletely understood. Recent studies reveal certain ?-3 FA derivatives actively attenuate and resolve inflammatory processes; these specialized pro-resolving mediators (SPM) may be key to the beneficial effects of ?-3 FA. Harnessing the protective properties of ?-3 FA and SPM in therapeutic strategies could revolutionize the way we combat debilitating airway diseases. However, it is not fully understood how ?-3 FA and SPM function in the lung to limit inflammation and promote resolution. Therefore, the objective of the proposed research is to determine the role of ?-3 FA and their SPM derivatives in modulating organic dust-induced airway inflammation. It is hypothesized that ?-3 FA and their SPM derivatives regulate the active resolution of airway inflammation following exposures to agricultural dusts. To test this hypothesis, three specific aims are proposed. The focus of aim 1 is to delineate the effects of ?-3 FA supplementation on mitigating organic dust-induced acute and chronic airway inflammation in vivo.
Aim 2 focuses on determining the mechanisms by which ?-3 FA exert anti-inflammatory and pro-resolving actions in organic dust-stimulated BECs.
Aim 2 a will determine the role of cyclooxygenase and lipoxygenase enzymatic pathways in regulating lipid mediator production in docosahexaenoic acid (DHA)-supplemented bronchial epithelial cells stimulated by DE.
Aim 2 b will define how DHA treatment alters TAK1-mediated inflammatory signaling in DE-stimulated BECs.
Aim 3 of the application examines how ?-3 FA regulates chronic organic dust-induced T cell and macrophage activation. These investigations are expected to have important positive impacts by demonstrating how ?-3 FA actively regulates lung inflammation resolution. These results will reveal the potential for interventions involving ?-3 FA supplementation in preventing and treating a broad array of inflammatory airway diseases. In addition to performance of the above proposed research aims, a major goal of this application is to provide training in the bioactive lipids field to aid in the candidate's successful transitio from a postdoctoral fellow to an independent investigator. Her long-term career objective is to become a successful, independent research investigator in academia. The candidate plans to develop a productive research program that adds depth and vitality to the field of environmental health research with a focus on immunity and natural, endogenous means of disease prevention and alleviation. Her NIEHS-F32 has provided training in environmental health and respiratory toxicology, while this K99 would allow her to develop expertise in bioactive lipid signaling and metabolism, including learning new techniques that will be critical to her success in this field. The candidate's academic research environment is well suited to providing her with the necessary training proposed in this application. The pulmonary research group at the University of Nebraska Medical Center has six NIH-, three CDC-, and two VA-funded basic research projects relevant to the candidate's proposed area of research training and investigation. The collaborative nature of the academic campus allows for frequent interfacing with basic scientists, clinicians, and other trainees on a daily basis. The Durham Research Center II built in 2009 includes state-of-the-art research core facilities and complete animal facilities available with th capacity to perform all advanced techniques described in the proposal. The candidate's proposed career development activities are aimed at bolstering her knowledge and experience in the bioactive lipids research field, and increasing her lab management and supervisory skills. During my K99 phase the candidate will work directly with Dr. Bruce Levy at the Harvard Medical School to learn how to prepare and handle samples for liquid chromatography-mass spectrometry technologies and analyze output for lipid metabolite profiling. She will participate i the Jackson Laboratory's The Whole Scientist 4-day workshop to bolster her skills and experience in mentoring, communication, lab management, and entrepreneurship. She will participate in the ATS postgraduate course, Using `omics to study lung disease to increase her capacity to derive robust, meaningful mechanistic data from the in vivo and other models utilized in my studies. The candidate plans to attend the 15th Eicosanoid Research Foundation's International Conference on Bioactive Lipids in Cancer Inflammation, and Related Diseases in addition to the annual ATS meetings. She will also attend relevant Keystone Symposia offered, i.e. the symposium on Systems Biology of Lipid Metabolism and/or the annual Kern Lipid Conferences, based on relevance. Throughout her K99 phase, she will continue to attend weekly lab meetings and departmental/relevant seminars, and present annually in departmental seminars as well as the Nebraska-Western Iowa Veterans Affairs Research Seminar Series. With this training program, the candidate will be able to transition to independence with expertise in a unique research niche investigating bioactive lipid metabolism and signaling in airway inflammation and resolution following environmental exposures.
The proposed studies are relevant to public health because they will demonstrate how dietary omega-3 fatty acids can be used in treating and preventing airway inflammation and disease caused by agriculture- related dust exposures. These experiments will lay the foundation for testing these fatty acids for their utility in other environmental exposure-related airway diseases, including those caused by diesel exhaust and other air pollutants. This project is relevant to the mission of NIEHS because the expected results will advance efforts in promoting healthier lives by potentially transforming how environmental exposure-related airway diseases are prevented and treated.
