Role of Src family kinases in hematopoietic proliferation and differentiation

Cleveland Clinic Lerner Com-Cwru, Cleveland OH

Investigators

Abstract

DESCRIPTION (provided by applicant): This proposal outlines a 5 year training program for the development of an academic career in Laboratory Medicine. The principle investigator has completed structured residency training in Clinical Pathology at the Cleveland Clinic, and will be joining the Dept. of Clinical Pathology as a junior faculty member in July 2008. Dr. Jaroslaw Maciejewski, a recognized leader in research involving hematopoietic disorders and bone marrow failure syndromes, will mentor the principal investigator's scientific development. He is the Head of the Experimental Hematology and Hematopoiesis Section. Through an NHLBI K24 grant, Dr. Maciejewski has created a research program in bone marrow failure syndromes that provides an exceptional environment for the proposed studies. In addtion, an advisory committee of experienced and highly-regarded physician scientists will provide scientific advice and career development guidance. The proposed studies attempt to define the role of lipid raft-associated Src family kinase (SFK) activity in certain myeloproliferative disorders characterized by aberrant activation of cytokine receptor signaling. The rationale for this proposal is based on the recognition that SFK are integral to many receptor signaling systems, and their intimate association with lipid raft signalosomes spatially targets them to interact with cytokine receptors. Our central hypothesis is that aberrantly active SFK associated with lipid raft microdomains lowers the threshold for cytokine receptor signaling, helping drive abnormal myeloproliferation. The proposed studies are significant in that they will identify the role of SFK in the pathogenesis of MPD, and develop novel diagnostic markers that will identify patients most likely to benefit from targeted kinase inhibitors. The Maciejewski laboratory is optimally equipped for the proposed studies. Access to patients with chronic MPD and MDS/MPD overlap syndromes is exceptional. The support of collaborators in the labs of Dr. Eric Hsi and Dr. Ram Ganapathi, and the excellent core facilities will ensure that technical challenges are appropriately addressed and resolved. In the process of executing the specific aims of this proposal, I will gain a comprehensive skill set that will facilitate my transition to an independent physician-scientist. RELEVANCE (See instructions): Myeloproliferative disorders, including classical MPD as well as myelodysplastic syndrome/MPD-overlap (MDS/MPD) are hematopoietic disorders that lead to significant morbidity and mortality and are often characterized by further transformation to acute myelogenous leukemia. Current therapy options are limited, and no curative treatments are available. The proposed studies will lead to discovery of aberrantly active signaling pathways that drive the disease identifying novel mechanisms of disease and therapeutic targets