) The academic career of the applicant has focused on clinical research in large granular lymphocyte (LGL) leukemia. An immediate career goal is to further develop clinical investigations in LGL leukemia with the long term objective being to understand the pathogenesis of the disease. The scientific environment and institutional support at Moffitt, a NCI designated cancer center, serve as a catalyst for accomplishment of these goals. LGL leukemia is a clonal lymphoproliferative disorder associated with neutropenia and autoimmune disease. Altered expression of Fas receptor (Fas) and Fas ligand is associated with lymphoproliferative and autoimmune diseases in animal models. Preliminary data suggest that dysregulation of the Fas-Fas ligand apoptotic pathway underlies the pathogenesis of LGL leukemia. Leukemic LGL, like T cells from Fas ligand transgenic mice, constitutively express high levels of Fas, yet are resistant to Fas-dependant apoptosis. Sera from LGL leukemia patients contain high levels of Fas ligand and cause apoptosis of normal neutrophils in a Fas-dependant fashion. We propose to investigate LGL leukemia as a model of dysregulated apoptosis causing human malignancy and autoimmune disease. An important component of the application is the development of a mentoring plan for beginning clinical investigators. Trainees with an interest in clinical investigation of LGL leukemia will be selected from the Clinical/Translational research fellowship training program at Moffitt. This training program is a structured mentored program with two pathways for hematology/oncology fellows aiming for an academic career as a clinical investigator. The first pathway includes didactic work leading to a M.P.H. degree in biostatistical/epidemiology. The second pathway is designed for in-depth mentored laboratory training and includes didactic course work in molecular biology and immunology. The work proposed is important not only for further understanding the pathogenesis of malignancies and autoimmune diseases, but also for providing training for clinical investigators in hematologic malignancies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Midcareer Investigator Award in Patient-Oriented Research (K24)
Project #
7K24CA083947-04
Application #
6647631
Study Section
Subcommittee G - Education (NCI)
Program Officer
Gorelic, Lester S
Project Start
2000-09-18
Project End
2005-08-31
Budget Start
2003-09-12
Budget End
2004-08-31
Support Year
4
Fiscal Year
2003
Total Cost
$126,381
Indirect Cost
Name
Pennsylvania State University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
Kothapalli, Ravi; Nyland, Susan B; Kusmartseva, Irina et al. (2005) Constitutive production of proinflammatory cytokines RANTES, MIP-1beta and IL-18 characterizes LGL leukemia. Int J Oncol 26:529-35
Epling-Burnette, Pearlie K; Bai, Fanqi; Wei, Sheng et al. (2004) ERK couples chronic survival of NK cells to constitutively activated Ras in lymphoproliferative disease of granular lymphocytes (LDGL). Oncogene 23:9220-9
Epling-Burnette, Pearlie Kay; Painter, Jeffrey S; Chaurasia, Pratima et al. (2004) Dysregulated NK receptor expression in patients with lymphoproliferative disease of granular lymphocytes. Blood 103:3431-9
Kothapalli, Ravi; Yoder, Sean J; Kusmartseva, Irina et al. (2003) Characterization of a variant of PAC-1 in large granular lymphocyte leukemia. Protein Expr Purif 32:52-60
Epling-Burnette, P K; Loughran Jr, Thomas P (2003) Survival signals in leukemic large granular lymphocytes. Semin Hematol 40:213-20
Kothapalli, Ravi; Bailey, Ratna D; Kusmartseva, Irina et al. (2003) Constitutive expression of cytotoxic proteases and down-regulation of protease inhibitors in LGL leukemia. Int J Oncol 22:33-9
Kothapalli, Ravi; Danyluck, Gregory M; Bailey, Ratna D et al. (2003) Problems associated with product enhancement reverse transcriptase assay using bacteriophage MS2 RNA as a template. J Virol Methods 109:203-7
Epling-Burnette, P K; Garcia, Roy; Bai, Fanqi et al. (2002) Carboxy-terminal truncated STAT5 is induced by interleukin-2 and GM-CSF in human neutrophils. Cell Immunol 217:1-11
Kothapalli, Ravi; Kusmartseva, Irina; Loughran, Thomas P (2002) Characterization of a human sphingosine-1-phosphate receptor gene (S1P5) and its differential expression in LGL leukemia. Biochim Biophys Acta 1579:117-23
Kothapalli, Ravi; Yoder, Sean J; Mane, Shrikant et al. (2002) Microarray results: how accurate are they? BMC Bioinformatics 3:22

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