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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23HL080077-04
Application #
7387328
Study Section
Special Emphasis Panel (ZHL1-CSR-Q (F3))
Program Officer
Scott, Jane
Project Start
2005-04-15
Project End
2010-03-31
Budget Start
2008-04-01
Budget End
2009-03-31
Support Year
4
Fiscal Year
2008
Total Cost
$150,721
Indirect Cost
Name
University of Rochester
Department
Internal Medicine/Medicine
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Tsang, Greg; Insel, Michael B; Weis, Justin M et al. (2016) Bioavailable estradiol concentrations are elevated and predict mortality in septic patients: a prospective cohort study. Crit Care 20:335
Wexler, Orren; Morgan, Mary A M; Gough, Michael S et al. (2012) Brachial artery reactivity in patients with severe sepsis: an observational study. Crit Care 16:R38
Gough, Michael S; Morgan, Mary Anne M; Mack, Cynthia M et al. (2011) The ratio of arginine to dimethylarginines is reduced and predicts outcomes in patients with severe sepsis. Crit Care Med 39:1351-8
Morgan, Mary Anne M; Frasier, Lauren M; Stewart, Judith C et al. (2010) Artery-to-vein differences in nitric oxide metabolites are diminished in sepsis. Crit Care Med 38:1069-77
Pietropaoli, Anthony P; Glance, Laurent G; Oakes, David et al. (2010) Gender differences in mortality in patients with severe sepsis or septic shock. Gend Med 7:422-37
Pietropaoli, Anthony; Georas, Steve N (2009) Resolving lung injury: a new role for Tregs in controlling the innate immune response. J Clin Invest 119:2891-4
Pietropaoli, Anthony P; Perillo, Irene B; Perkins, Peter T et al. (2007) Smokers have reduced nitric oxide production by conducting airways but normal levels in the alveoli. Inhal Toxicol 19:533-41