This proposal describes a training program to enhance the scientific and technical skills of the principal investigator for a successful career in an academic institution. The proposed research will shed more light on cell death research as it relates to hematological malignancies. The University of Massachusetts Medical School provides a sound setting for the training of postdoctoral fellows by incorporating expertise from diverse resources into a customized training. Dr. Michael R. Green, who has trained numerous postdoctoral fellows, will mentor the principal investigator's scientific development. To further enhance this program, the principal investigator has enlisted the expertise of Drs. Castilla and Kelliher, who pioneered bone marrow transplantation techniques to analyze leukemia in mice. The long-term goal of this research is to investigate, at the molecular level, the way cells commit suicide following growth factor deprivation, the way this process is subverted in neoplastic disease, and the ways which we may manipulate those regulatory processes to fight cancer. Recent work demonstrated that loss of cytokine signaling triggers the secretion of lipocalin 24p3, which then binds to a cell-surface receptor and induces apoptosis. Lipocalin 24p3 is an iron-binding protein and the iron content of 24p3 is an essential determinant in the induction of apoptosis. Research will focus on the 24p3 death-signaling pathway, and analyzing the role of 24p3 in the development of leukemia in mouse models.
The specific aims are: 1) To establish the relationship between iron chelation and induction of apoptosis by 24p3 and identify the 24p3 death-signaling pathway and 2) To assess the roles of 24p3 and its receptor in human hematological malignancies. Proposed experiments will entail the analysis of gene expression in 24p3 treated cells using microarrays and transplantation of BCR/ABL transduced bone marrow cells into 24p3 null mice and subsequent phenotypic analysis using a variety of biochemical, cellular and molecular techniques.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01CA113838-06
Application #
7877049
Study Section
Subcommittee G - Education (NCI)
Program Officer
Lohrey, Nancy
Project Start
2006-07-01
Project End
2012-06-30
Budget Start
2010-07-01
Budget End
2012-06-30
Support Year
6
Fiscal Year
2010
Total Cost
$145,750
Indirect Cost
Name
Case Western Reserve University
Department
Pathology
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Davuluri, Gangarao; Song, Ping; Liu, Zhuoming et al. (2016) Inactivation of 3-hydroxybutyrate dehydrogenase 2 delays zebrafish erythroid maturation by conferring premature mitophagy. Proc Natl Acad Sci U S A 113:E1460-9
Porwal, Suheel K; Furia, Emilia; Harris, Michael E et al. (2015) Synthetic, potentiometric and spectroscopic studies of chelation between Fe(III) and 2,5-DHBA supports salicylate-mode of siderophore binding interactions. J Inorg Biochem 145:1-10
Liu, Zhuoming; Ciocea, Alieta; Devireddy, L (2014) Endogenous siderophore 2,5-dihydroxybenzoic acid deficiency promotes anemia and splenic iron overload in mice. Mol Cell Biol 34:2533-46
Liu, Zhuoming; Velpula, Kiran K; Devireddy, Lax (2014) 3-Hydroxybutyrate dehydrogenase-2 and ferritin-H synergistically regulate intracellular iron. FEBS J 281:2410-21
Liu, Zhuoming; Petersen, Robert; Devireddy, Laxminarayana (2013) Impaired neutrophil function in 24p3 null mice contributes to enhanced susceptibility to bacterial infections. J Immunol 190:4692-706
Liu, Zhuoming; Lanford, Robert; Mueller, Sebastian et al. (2012) Siderophore-mediated iron trafficking in humans is regulated by iron. J Mol Med (Berl) 90:1209-21
Pantopoulos, Kostas; Porwal, Suheel Kumar; Tartakoff, Alan et al. (2012) Mechanisms of mammalian iron homeostasis. Biochemistry 51:5705-24
Liu, Zhuoming; Yang, Amy; Wang, Zhengqi et al. (2011) Multiple apoptotic defects in hematopoietic cells from mice lacking lipocalin 24p3. J Biol Chem 286:20606-14