This proposal aims at providing the principal investigator with a training program for the development of a career as a translational researcher in Critical Care Medicine. Before becoming an Assistant Professor in Critical Care Medicine at the University of Pittsburgh, the principal investigator has completed a structured residency in Anesthesiolgy as well as a structured fellowship in Critical Care Medicine. Sepsis remains a leading cause of mortality in the United States. It is most frequently caused by pulmonary infections. New onset of acute renal failure (ARF) during early sepsis greatly increases the morbidity and mortality of sepsis. Experimental data suggest that the devastating effects of ARF in the critical care setting involve modulation of the inflammatory response. However, the exact mechanism by which ARF affects remote organ (dys-) function during bacterial infections is largely unknown. The proposed studies aim at unraveling the effect of ARF on bacterial pneumonia, the most frequent cause of sepsis and subsequent ICU admission. The principal investigator has therefore formulated a hypothesis under two interrelated specific aims.
In specific aim 1, the principal investigator will test the hypothesis that ARF worsens the course of bacterial pneumonia in a murine model of P. aeruginosa pneumonia. Special emphasis will be given to the role of neutrophils.
In specific aim 2, the principal investigator will test the hypothesis that ARF affects the homeostasis of the leukocyte adhesion molecule L-selectin and thereby modulates neutrophil recruitment to the lungs during pneumonia. In a pilot study, the principal investigator will also test the hypothesis that these findings are true for patients with septic shock and ARF in vitro. These studies will advance our knowledge of the mechanisms giving rise to the extremely poor outcome of patients with sepsis and ARF. The findings may lay groundwork for future preventive or therapeutic strategies. This proposal is designed to provide the principal investigator with the resources and training necessary to achieve the following goals. First, it will allow the principal investigator to become a successful and independent clinician scientist in critical care medicine. Secondly, it will allow the principal investigator to advance my knowledge of the effects of ARF in the setting of sepsis. It will serve as a scaffold to obtain additional training in methods crucial for successful translational research, including design and execution of studies with human subjects as well as expertise and technical skills in the field of bacteria-host interactions as they pertain to sepsis research. The proposed activities will enable the principal investigator to acquire knowledge and expertise necessary to address clinically relevant problems 'at the bench'and validate the findings in clinical practice. A detailed plan fnr Hiriartir training with formal rnnrep wnrk ha"""""""";hppn InrliiHpH
|Singbartl, Kai; Miller, Lauren; Ruiz-Velasco, Victor et al. (2016) Reversal of Acute Kidney Injury-Induced Neutrophil Dysfunction: A Critical Role for Resistin. Crit Care Med 44:e492-501|
|Wen, Xiaoyan; Peng, Zhiyong; Li, Yingjian et al. (2012) One dose of cyclosporine A is protective at initiation of folic acid-induced acute kidney injury in mice. Nephrol Dial Transplant 27:3100-9|
|Peng, Zhi-Yong; Wang, Hong-Zhi; Srisawat, Nattachai et al. (2012) Bactericidal antibiotics temporarily increase inflammation and worsen acute kidney injury in experimental sepsis. Crit Care Med 40:538-43|
|Singbartl, Kai; Bishop, Jeffery V; Wen, Xiaoyan et al. (2011) Differential effects of kidney-lung cross-talk during acute kidney injury and bacterial pneumonia. Kidney Int 80:633-44|
|Rossaint, Jan; Spelten, Oliver; Kassens, Nadja et al. (2011) Acute loss of renal function attenuates slow leukocyte rolling and transmigration by interfering with intracellular signaling. Kidney Int 80:493-503|