? ? Gram-negative bacterial pneumonia is a growing specter in the realm of nosocomial infections. Increasing drug resistant strains loom ominously over the infirm and immunocompromised. A better understanding of host-pathogen interactions will elucidate alternative therapies to antibiotics. This proposal will support the Principal Investigator in the study of lipocalin 2, a host-derived molecule with bacteriostatic properties mediated through a novel mechanism. Lipocalin 2 acts as a receptor for siderophores - bacterial-derived proteins that scavenge miniscule amounts of free iron needed for bacterial metabolism. The role of lipocalin 2 in Gram-negative bacterial pneumonia will be studied in a mouse model of Klebsiella pneumoniae infection.
Research Aims : (1) Characterize the regulation of lipocalin 2 during K. pneumoniae lung infection. Molecular regulation of lipocalin 2 will be tested using mice deficient in signaling molecules believed to be important for its upregulation. The P.I. will identify which cells express lipocalin 2 using immunofluorescence microscopy and bone marrow chimeras. (2) Determine the function of lipocalin 2 during K. pneumoniae lung infection. Lipocalin 2 gene knockout animals will undergo bacterial challenge and clinical outcomes compared to wildtype infected animals. Recombinant Lipocalin 2 will be synthesized and administered to lipocalin 2 deficient animals to """"""""rescue"""""""" the infection-susceptible phenotype. Career Goals: This proposal details a five-year plan that will help the P.I. characterize mechanisms of host immune defense and achieve the following: (1) Expand the candidate's immunology knowledge in order for her to become a world class researcher in the field of innate immunity. (2) Increase the sophistication of the candidate's laboratory expertise including advanced microscopy techniques, bone marrow chimera generation, and recombinant protein chemistry. 3) Develop professional skills to conduct independent investigation in a collaborative environment through didactics:and experiential learning.

Public Health Relevance

""""""""Influenza and Pneumonia"""""""" was the 8th leading cause of death in the 2006 National Vital Statistics Report. Chronic lower respiratory diseases and pneumonitis due to aspiration, were separately listed leading causes of death. However, pneumonia is a frequent complication leading to the demise of these patients as well. Taken together, pneumonia remains a leading killer despite the antibiotic era. Therefore, a better understanding otthe innate immune response protein Lipocalin 2 will shed light on alternative therapies to fight bacterial pneumonia. ? (End of Abstract) ? ? ? ? ?

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-O (M1))
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Colombini-Hatch, Sandra
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University of Pittsburgh
Internal Medicine/Medicine
Schools of Medicine
United States
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Chan, Yvonne R; Chen, Kong; Duncan, Steven R et al. (2013) Patients with cystic fibrosis have inducible IL-17+IL-22+ memory cells in lung draining lymph nodes. J Allergy Clin Immunol 131:1117-29, 1129.e1-5
Chan, Yvonne R; Liu, Jessica S; Pociask, Derek A et al. (2009) Lipocalin 2 is required for pulmonary host defense against Klebsiella infection. J Immunol 182:4947-56
Kolls, Jay K; McCray Jr, Paul B; Chan, Yvonne R (2008) Cytokine-mediated regulation of antimicrobial proteins. Nat Rev Immunol 8:829-35