This project provides a carefully organized training program and a focused research project that will enable the candidate to pursue a career as an independent clinician-scientist. Training/Environment: The candidate has and previous basis science training as a graduate student and subsequently completed veterinary school, residency and subspecialty clinical training. The program outlined in this application involves a new direction for the candidate, focusing on basic molecular mechanisms regulating the inflammatory response in oxidant-induced lung injury. The scientific mentor, Dr. Steven Albelda, and members of the advisory advisory committee will emphasize molecular biology laboratory skills not included in prior training. The academic environment provides important seminar lectures and selected graduate-level courses to supplement the laboratory work. The advisory committee will meet on a regular basis to mentor the applicant throughout the training period. Her limited clinical activities as an anesthesiologist working in the surgical and intensive care areas with a focus on evaluation and treatment of patients with cardiopulmonary dysfunction, will complement her basic science investigation. Research Plan: Research will focus on understanding the molecular mechanisms of pulmonary toxicity due to prolonged exposure to high oxygen concentrations oxygen using a mouse model of hyperoxic lung injury. The hypothesis to be tested is that endothelial cell activation/injury and initiation of neutrophil/endothelial interactions play a prominent role in the development of lung injury during prolonged oxygen exposure. This will be investigated in three specific aims:
In Aim 1, the candidate will determine the pattern of endothelial-specific gene expression during hyperoxia and how endothelial cell activation/injury contributes to the development of the inflammatory response and oxygen-induced lung injury. This will be accomplished by creating and studying an endothelial selective gene expression profile using array technology and by delivering intracellular antioxidants directly to endothelial cells.
In Aim 2, the candidate will evaluate if the inflammatory cascade plays a central role in the development of oxygen-induced lung injury. This will be accomplished by gene expression analysis, neutrophil depletion experiments, and use of blocking antibodies in NFKB-knockout mice.
In Aim 3, the candidate proposes to use array technology to identify new genes expressed in oxygen toxicity and generate new hypotheses regarding molecular mechanisms of oxygen-induced injury. Using this technology, the candidate has identified changes in thrombornodulin expression in the lung in response to hyperoxia, leading to new hypotheses to be tested in this aim regarding the role of the coagulation cascade and, more specifically, the activated protein C pathway during hyperoxia. It is proposed that this combination of training and research will allow the candidate to transition to a fully independent research investigator, retaining ties to the veterinary community.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Clinical Investigator Award (CIA) (K08)
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Special Emphasis Panel (ZHL1-CSR-M (F2))
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Colombini-Hatch, Sandra
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University of Pennsylvania
Other Clinical Sciences
Schools of Veterinary Medicine
United States
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Perkowski, Sandra; Scherpereel, Arnaud; Murciano, Juan-Carlos et al. (2006) Dissociation between alveolar transmigration of neutrophils and lung injury in hyperoxia. Am J Physiol Lung Cell Mol Physiol 291:L1050-8
Perkowski, Sandra; Sun, Jing; Singhal, Sunil et al. (2003) Gene expression profiling of the early pulmonary response to hyperoxia in mice. Am J Respir Cell Mol Biol 28:682-96