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.
