PROJECT SUMMARY
This Mentored Clinical Scientist Research Career Development Award (K08) proposal describes a five-year
training program to support Ji Young Lee, an MD/PhD pulmonologist/intensivist, for her research-intensive
independent physician-scientist career. The primary mentor, Dr. Troy Stevens, a world leader in the field of lung
biology with a track record of excellence in training junior faculty, and the advisory committee consisting of
accomplished researchers with diverse expertise, will provide scientific feedback and career guidance
throughout the award period. The proposed work will be carried out at the highly interdisciplinary and well-funded
Center for Lung Biology, a strength of the University of South Alabama. The candidate was recently appointed
as assistant professor of Physiology and Cell Biology and Internal Medicine on the tenure-accruing investigator
track with 75% of protected research time. Twenty five percent time is allocated for clinical activities in the division
of pulmonary and critical care medicine, where she is facilitating translational research. The career development
plan lays out didactic coursework, scientific meetings and professional development opportunities that will help
the candidate obtain core knowledge and scientific communication and academic leadership skills, and develop
R01 funding. The proposed research plan focuses on improving our understanding of the effects of acidosis on
pneumonia, and establishing the conceptual basis for diagnostic and therapeutic translation. Acidosis is common
in critically ill pneumonia patients, and is associated with high mortality. The pathophysiology of acidosis in
pneumonia is poorly understood, and current therapies fail to improve major outcomes. Our studies have shown
that pulmonary microvascular endothelial cells (PMVECs) utilize the carbonic anhydrase IX (CA IX) isoform to
regulate pH, metabolism and migration. We also demonstrated that Pseudomonas aeruginosa infection of
PMVECs induces release of cytotoxic amyloid proteins, which disrupts the alveolar capillary membrane. These
cytotoxic amyloids induce soluble CA IX shedding from PMVECs which compromises their repair potential.
Based on these preliminary studies, we test the hypothesis that P. aeruginosa infection induces cytotoxic amyloid
production that leads to shedding of soluble CA IX in PMVECs, increasing lung injury. Specific aims test the
hypotheses that: 1) CA IX is critical to the acid regulation, metabolism and migration of PMVECs and pulmonary
endothelial barrier integrity; and, 2) P. aeruginosa infection elicits cytotoxic amyloid production, causing CA IX
shedding in PMVECs, which increases lung injury. In vitro, we will use genetic approaches and endothelial cell
functional assays to evaluate the effects of acidosis and the role of specific CA IX functional domains during
physiologic and infectious conditions. In vivo and ex vivo, we will use acidosis, pneumonia and isolated lung
perfusion mouse models to translate in vitro findings. Successful completion of this study will provide new insights
into the mechanisms underlying acidosis in pneumonia and help identify CA IX and cytotoxic amyloids as
biomarkers and therapeutic targets for pneumonia.