Homeostasis of the immune system is maintained through a balance of pro-life and pro-death signals, with availability of the cytokine, interleukin-7 (IL-7), a critical resource limiting population size. Cell death is a necessary process that eliminates abnormal cells in healthy tissue. Cell growth is mediated by regulation of the cell life cycle and metabolism. By exploring these biological activities of IL-7, this proposal expands the understanding of the origins of cancer. Key findings from the proposed studies will be developed into an innovative research program designed to study the role of IL-7 in lymphomagenesis. The hypothesis to be tested is that IL-7 promotes life by repressing apoptotic proteins of the BCL-2 family, while regulating cell cycling through the phosphatase, Cdc25A, and maintaining metabolic resources through glucose uptake. Loss of IL-7 triggers the apoptotic protein, BAX, which is inhibited by BCL-2. Studies suggest that the apoptotic protein, BIM, could be a target of IL-7 signaling and modulate the effector activities of BAX and BCL-2. This will be determined by examining the activity of BIM in lymphocytes - how IL-7 regulates BIM and how BIM interacts with other BCL-2 family members. The activity of IL-7 as a proliferative factor will be studied by examining the regulation and function of the phosphatase, Cdc25A, a key mediator of cell cycling. To establish the homeostatic potential of Cdc25A, cells expressing an active, stable form of Cdc25A will be evaluated for growth in an IL-7 deficient environment. The survival and proliferative activities of IL-7 may be supported by maintenance of energy resources. The factors mediating glucose uptake through IL-7 signaling will be examined in cells in which apoptosis has been inhibited or cell division induced. The approaches proposed combine the use of mouse experiments that establish physiological relevance with functional assays using cell lines to examine mechanisms underlying the activities of IL-7 essential for the homeostasis of peripheral cells. Expected findings will have significant impact in field of cytokine research. ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA109524-03
Application #
7473259
Study Section
Cellular and Molecular Immunology - B (CMI)
Program Officer
Mccarthy, Susan A
Project Start
2006-09-01
Project End
2010-07-31
Budget Start
2008-08-01
Budget End
2009-07-31
Support Year
3
Fiscal Year
2008
Total Cost
$195,792
Indirect Cost
Name
University of Central Florida
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
150805653
City
Orlando
State
FL
Country
United States
Zip Code
32826
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Ruppert, Shannon M; Chehtane, Mounir; Zhang, Ge et al. (2012) JunD/AP-1-mediated gene expression promotes lymphocyte growth dependent on interleukin-7 signal transduction. PLoS One 7:e32262
Boohaker, Rebecca J; Zhang, Ge; Carlson, Adina Loosley et al. (2011) BAX supports the mitochondrial network, promoting bioenergetics in nonapoptotic cells. Am J Physiol Cell Physiol 300:C1466-78
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