This proposal outlines a 5-year training program in molecular pathology in preparation for an academic career. The applicant is a physician with specialty training in hematology/oncology who is currently completing the requirements for a PhD in Molecular Pathology at the University of Washington. The graduate training in pathology has provided him with basic research experience and tools in addition to his clinical skills. The integrated support by oncology, pathology, and molecular biology and the co-mentorship of Dr. Deeg and Dr. Hockenbery provide an excellent basis for the applicant to acquire the expertise needed for an innovative investigator in the field. The participation of experts on regulation of cell death (Dr. Hockenbery) and hematopoiesis (Dr. Torok-Storb), molecular pathology (Dr. Radich), genetic manipulations (Dr. Kiem), oncogenesis (Dr. Kemp), and biostatistics (Dr. Gooley) will greatly enhance training sophistication, efficacy and productivity. The proposal is aimed at elucidating the pathophysiology of the myelodysplastic syndromes (MDS). A prominent characteristic of MDS is dysregulation of programmed cell death (apoptosis). Apoptosis rates are high in low-grade MDS, whereas in advanced MDS clonal hematopoietic stem/progenitor cells (HPC) tend to be resistant to apoptosis. The proposed studies focus on the role of marrow stroma in providing signals that render clonal HPC sensitive to apoptosis induced by biological ligands such as tumor necrosis factor alpha (TNF() and chemotherapeutic agents. Preliminary data show that the transcription factors, DJ-1 and TWIST, both of which interfere with p53 function, are upregulated in HPC from advanced MDS. Contact with stroma results in downregulation of these two factors and sensitivity to apoptosis. No apoptosis sensitivity is induced, however, in HPC from healthy individuals.
The specific aims, therefore, are. 1) Characterize the role of DJ-1 for survival of clonal and non-clonal HPC in MDS by determining the effects of DJ-1 on p53-mediated apoptosis. 2) Define the effect of DJ-1 on PYCARD, a pro-apoptotic adaptor downstream of p53, and the survival of clonal and non-clonal HPC. 3) Determine the expression of the transcription factor, TWIST, and characterize its effect on apoptosis in MDS marrow;a) characterize the role of TWIST in stroma cells;b) characterize the role of TWIST in HPC. These studies are expected to provide basic insights into the regulation of apoptosis in clonal HPC and into the pathophysiology of MDS. This, in turn, may lead to the identification of targets for novel therapeutic interventions. The Fred Hutchinson Cancer Research Center together with investigators at the Seattle Cancer Care Alliance and the University of Washington provides an ideal environment in which to accomplish the proposed objectives and to foster the career of a young investigator.
A better understanding of the regulation of cell death in the proposed model should lead to more specific and effective therapy of clonal and inflammatory diseases. An investigator trained in both clinical and basic research is in the best position to succeed in this endeavor.
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