DESCRIPTION (provided by applicant): My interest in human health and how the body reacts to the pressure of our environment and behaviors began in graduate school. In masters level study, I had the opportunity to participate in research projects, which gave me insight into how human body reacts negatively to certain environmental and occupational pressures. After earning my MPH, I completed a PhD from Florida A&M University in Toxicology, revealing to me the basic understanding that the small airways and alveolar spaces based on their innate function and purpose could be the anatomical equivalent of a triangle of environmental insult, innate response and human behavior. I accepted a postdoctoral research fellowship at the University of Nebraska Medical Center in October 2009, and in January 2012, I accepted an assistant professor faculty position in the UNMC College of Public Health, Department of Environmental, Agricultural and Occupational Health (EAOH). To date I have utilized my Toxicology/Public Health academic training and professional experiences to publish two additional manuscripts with my colleagues and composed a grant that was funded for one year from the Nebraska Department of Health and Human Service to investigate avenues to chemo prevent DNA adduct formation in ethanol and cigarette exposed pulmonary tissue. While preparing to become a R01-funded basic scientist, the proposed K01 support will assist in conducting more comprehensive and scientifically relevant research on the xenobiotic effects of lung antimicrobial peptide production along with resulting in a better understanding of ethanol- mediated p450 activity. I am supported by a very productive, accomplished and dedicated Advisory Committee led by Co-mentors Dr. Todd Wyatt, a leader in ethanol metabolic cilia and pulmonary dysfunction, who has been continuously NIH- and VA-funded for the last 15 years, and Dr. Jill Poole, an R01-funded clinician/scientist/immunologist currently investigating vitamin D and immune responses. My other advisory committee members are Drs. Whitney Goldner and Robert Heaney, a clinician-scientist investigating associations of vitamin D and thyroid cancer, and an extremely well published and recognized leader in the field of vitamin D translational research for decades, respectively. My goal is to be a board-certified academic toxicologist able to conduct scientifically sound, basic and translational research projects with a emphasis in pulmonary health. To accomplish this goal, I propose to A) become a Diplomat of the American Board of Toxicology; B) become competent in structuring, implementing, and analyzing translational research projects by participating in the UNMC clinical and translational training program; and C) continue professional development as a junior faculty member in the UNMC College of Public Health through scholarly training, research contributions and didactic instruction. Based on our own preliminary data and published work describing the role of ethanol in increased respiratory infection rates and severity, ARDS, and burn recovery complications, we hypothesize that ethanol decreases antimicrobial lung protection through the dysregulation of vitamin D. I will investigate this hypothesis by investigating three specific aims 1) characterize antimicrobial peptide LL-37 levels in response to both in vitro and in vivo ethanol exposure, 2) identify mechanisms by which ethanol modulates antimicrobial peptides, and 3) determine the functional consequences of ethanol on antimicrobial peptide LL-37 perturbations using an in vivo lung infection model. The NHLBI K01 would strongly boost the quality, and quantity, of my research in the area of ethanol dysmetabolism of vitamin D activation by providing protected time and allowing for further career development. (End of Abstract)

PROJECT NARRATIVE From increased risk of mortality in hemodialysis patients to increased respiratory infections and reduced recovery rates in severely burned alcoholics, LL-37 presence and function has become clearly integral in maintaining proper human health. This proposal answers the question of how ethanol exerts its inhibitory effect on LL-37 production. This proposal will shed light on the mechanisms by which ethanol perturbs LL-37 function by detailing where in the vitamin D pathway ethanol is exerting its effect while identifying potential therapeutic pathways to attenuate negative ethanol-related health outcomes.