The purpose of this Mentored Patient-Oriented Research Career Development Award is to become an independent investigator with expertise in translational studies linking basic aspects of critical illness pathophysiology to clinical outcomes. This proposal details a structured plan for accomplishing this long term goal, through a series of short-term career development steps occurring simultaneous with a clinical study of septic patients. The backbone of the career development plan involves didactic training throughout the Masters in Public Health Program and the Rochester Clinical Research Curriculum, coupled with one-on-one mentoring with experts in clinical research, endothelial and vascular function, sepsis, biostatistics, and risk adjustment/ outcomes research. The objective of the research component of this proposal is to determine whether gonadal hormone concentrations predict oxidant stress, endothelial function and clinical outcome in patients with sepsis. These studies will test the hypothesis that estrogen is associated with superior endothelial function resulting from reduced oxidant stress and enhanced vascular nitric oxide bioactivity. These studies will also test the hypothesis that these estrogen-mediated vascular responses are associated with improved clinical outcomes in septic patients. The first goal of these studies will be to determine relationships between gonadal hormone concentrations, endothelial function, nitric oxide metabolism, and reactive oxygen species generation. The second goal will be to determine the relationship of these physiologic measurements to short and long term clinical outcomes. By performing these studies, we hope to learn the pathophysiologic basis for the epidemiologic findings of lower sepsis incidence rates and improved clinical outcomes in women compared to men. If our hypothesis is confirmed, these studies will provide a clear rationale for short-term estrogen replacement therapy in sepsis.
