In this mentored clinical scientist training proposal, the applicant will test the hypothesis that probiotic and commensal bacterial organisms secrete soluble, heat-labile proteins exert their beneficial effects by the induction of cytoprotective heat shock proteins (hsp) and the inhibition of the proinflammatory NF-kappaB pathway in gut epithelial cells. Preliminary data strongly support this hypothesis and show feasibility of proposed approaches. Studies are aimed at examining specific mechanisms of probiotic action, the relative roles of the aforementioned actions in mediating probiotic action, and identifying bioactive probiotic proteins. These investigations will provide an outstanding training opportunity for the applicant to learn how to examine transcriptional and post-transcriptional processes, learn epithelial biology, and acquire additional skills in molecular and cell biology, including imaging technology. Finally, the applicant will learn biochemical techniques to identify and purify the active components of the bacterial conditioned media. The applicant, Elaine O. Petrof, MD, M.Sc., completed her Infectious Diseases fellowship and went on to pursue a Clinical Pharmacology fellowship at the University of Chicago. During this period, she entered the IBD laboratory of Dr. Eugene Chang to seek additional basic science training and to study the effect of probiotics and commensal flora on gut epithelium. The proposed training plan provides 75% protected time, numerous opportunities to acquire new skills and experience in cell and molecular biology, didactic training in techniques and proper conduct in research, meaningful interactions with other experienced investigators, and phased transition steps for the applicant to mature as an independent investigator. The applicant's research will form a solid foundation for future research required to develop a career in academic medicine

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08DK064840-03
Application #
6899258
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Podskalny, Judith M,
Project Start
2003-09-15
Project End
2008-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
3
Fiscal Year
2005
Total Cost
$124,848
Indirect Cost
Name
University of Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Shiou, Sheng-Ru; Yu, Yueyue; Guo, Yuee et al. (2013) Synergistic protection of combined probiotic conditioned media against neonatal necrotizing enterocolitis-like intestinal injury. PLoS One 8:e65108
Petrof, Elaine O; Claud, Erika C; Sun, Jun et al. (2009) Bacteria-free solution derived from Lactobacillus plantarum inhibits multiple NF-kappaB pathways and inhibits proteasome function. Inflamm Bowel Dis 15:1537-47
Petrof, Elaine O; Musch, Mark W; Ciancio, Mae et al. (2008) Flagellin is required for salmonella-induced expression of heat shock protein Hsp25 in intestinal epithelium. Am J Physiol Gastrointest Liver Physiol 294:G808-18
Claud, Erika C; Zhang, Xiaoqiong; Petrof, Elaine O et al. (2007) Developmentally regulated tumor necrosis factor-alpha induced nuclear factor-kappaB activation in intestinal epithelium. Am J Physiol Gastrointest Liver Physiol 292:G1411-9
Tao, Yun; Drabik, Kenneth A; Waypa, Tonya S et al. (2006) Soluble factors from Lactobacillus GG activate MAPKs and induce cytoprotective heat shock proteins in intestinal epithelial cells. Am J Physiol Cell Physiol 290:C1018-30
Petrof, Elaine O; Ciancio, Mae J; Chang, Eugene B (2004) Role and regulation of intestinal epithelial heat shock proteins in health and disease. Chin J Dig Dis 5:45-50
Musch, Mark W; Petrof, Elaine O; Kojima, Keishi et al. (2004) Bacterial superantigen-treated intestinal epithelial cells upregulate heat shock proteins 25 and 72 and are resistant to oxidant cytotoxicity. Infect Immun 72:3187-94
Petrof, Elaine O; Kojima, Keishi; Ropeleski, Mark J et al. (2004) Probiotics inhibit nuclear factor-kappaB and induce heat shock proteins in colonic epithelial cells through proteasome inhibition. Gastroenterology 127:1474-87