The candidate is an academic gastrointestinal surgeon whose career objective is to become an independently funded clinician-scientist. He undertook a two-year research fellowship during surgical residency at the University of Michigan that provided preliminary experience in tumor biology and genetics, and instilled a strong desire to become a clinician scientist and an innovator in treatment of gastrointestinal malignancies. To develop his research career, the candidate needs significantly more time for scientific pursuits as well as the mentorship of experienced scientists. His career development plan includes both didactic and practical studies in the regulation of protein trafficking with the supervision of highly successful and innovative scientists at the University of Pittsburgh. The environment provided in the Department of Surgery is outstanding and has already trained numerous accomplished clinician-scientists. The sponsors have dedicated their laboratory resources, equipment, and time to ensure the candidate's success. The research plan focuses on improving our understanding of the cellular regulation of the death receptor Fas and differences in this regulation that may be important to the pathogenesis of Barrett's Esophagus (BE) and esophageal adenocarcinoma (EA). We have recently shown decreased cell surface expression of Fas in BE with dysplasia and EA suggesting alterations in Fas trafficking occur frequently and early in EA tumorigenesis. Surprisingly, very little is known about how cell-surface expression of Fas is regulated. We hypothesize that Fas protein degradation and trafficking of the receptor to and from the cell surface are important mechanisms of regulation, and that differences in this regulation exist between squamous esophageal epithelium and BE that contribute to the pathogenesis of BE and the associated risk of malignant transformation. To test these hypotheses, we propose two specific aims to examine Fas protein trafficking events and make comparisons of Fas expression and response to various stimuli in an immortalized esophageal epithelial cell line (HET-1A), primary cultures of esophageal squamous epithelium and BE, and EA cell lines (Seg-1, Bic-1, and Flo-1).
Aim 1 : To determine the cellular mechanisms involved in the regulation of Fas protein delivery to the cell surface in esophageal epithelia and adenocarcinoma cells.
Aim 2 : To determine the cellular mechanisms involved in the regulation of Fas protein stability at the cell surface in esophageal epithelia and adenocarcinoma cells. Improving our understanding of the cellular mechanisms that regulate Fas trafficking and turnover, cell-type specific differences in this regulation, and alterations that occur in malignancy could lead to effective, novel therapies for gastrointestinal malignancies and possibly many other diseases. This improved understanding may also alter the current management of gastroesophageal reflux disease, BE, and EA.
|Naran, Sanjay; Abrams, Peter; de Oliveira, Pierre Queiroz et al. (2011) Bile salts differentially sensitize esophageal squamous cells to CD95 (Fas/Apo-1 receptor) mediated apoptosis. J Surg Res 171:504-9|
|Mahidhara, Raja S; Queiroz De Oliveira, Pierre E; Kohout, Jaromir et al. (2005) Altered trafficking of Fas and subsequent resistance to Fas-mediated apoptosis occurs by a wild-type p53 independent mechanism in esophageal adenocarcinoma. J Surg Res 123:302-11|