Our proposal details a 5-year training program designed to facilitate development of the applicant into an independent clinician research scientist with expertise in alcohol's effects on pulmonary host defenses. Having completed his fellowship in Pulmonary and Critical Care Medicine, the applicant will join the LSU faculty as an assistant professor in January 2004. He is now finishing post-doctoral training in the basic research facilities of the LSU Alcohol Research Center, where his current focus involves alcohol's effect on the development of a coordinated host defense response to bacterial pneumonia. Through inhibition of cytokines such as IL-12 which functionally link innate and adaptive immunity, alcohol intoxication worsens the outcome from bacterial pneumonia, increasing patient morbidity and mortality. IL-23 and IL-27 are recently identified cytokines similar to, but distinct from, IL-12 in their roles as soluble messengers between cellular components of innate and adaptive immunity. This research proposal is focused on novel mechanisms through which alcohol intoxication can disrupt the normal interface between innate and adaptive immune responses to bacterial infection in the lung. Specifically, alcohol's effect on IL-23 and IL-27 expression during pulmonary infection with Klebsiella pneumoniae will be studied.
Our specific aims will address: 1) the in vivo and in vitro ability of alcohol to suppress pulmonary IL-23/IL-27 gene and protein expression during K. pneumoniae infection 2) the relationship between alcohol's effects on IL-23/IL-27 and its modulation of a) NF-KappaB and b) IL-10 expression during infection 3) the ability of recombinant interferongamma to attenuate alcohol's effects on IL-23 and IL-27 in response to K. pneumoniae and 4) the ability of locally delivered IL-23 or IL-27 gene therapy to improve the outcome of pulmonary infection with K. pneumoniae during alcohol intoxication. This work entails novel basic research which will also serve as a vehicle through which the applicant will learn specific techniques of alcohol modeling, bacteriology, immunology, molecular biology, and gene therapy. As such, these experiments will be performed in the highly productive environment of the LSU Alcohol Research Center laboratories. The didactic program and basic research experiences in this mentored proposal are designed to catalyze the applicant's development into an independent investigator in the field of alcoholism and pulmonary host defenses.
