This proposal is designed to provide the Principal Investigator, Manoj Pillai, with a training experience that combines basic science research with clinical research. Basic studies focus on the role of monocyte-derived chemokines in the regulation of hematopoiesis, using in-vitro systems that model the marrow microenvironment (ME). Clinical correlates come from a comparative analysis of normal monocytes with those from patients with myelodysplastic syndrome (MDS), where abnormal monocyte function may be associated with pathogenesis. The training program involves scientific investigation and didactic study under the mentorship of Dr. Beverly Torok-Storb and Dr. Rainer Storb. The candidate will also benefit from the guidance of Dr. Joachim Deeg and Dr. Larry Rohrschneider, who will be part of his advisory committee. The regulation of hematopoiesis is complex, involving several different cell types, working in concert in the context of the ME. Preliminary data indicate that monocytes, which are an integral component of the ME secrete a chemokine, CXCL7, in response to stromal signals. CXCL7 peptides, previously reported to be derived only from cells of the megakaryocyte lineage, are reported to augment fibroblast growth and inhibit platelet production. The proposed studies will test the hypothesis that stromal-stimulated monocyte-derived CXCL7 peptides also affect the function of the ME. In addition, given that preliminary data suggest abnormal CXCL7 gene expression in monocytes from MDS patients, a second hypothesis to be tested is that abnormal patterns of CXCL7 expression in monocytes may contribute to pathogenesis in these patients.
Three Specific Aims are proposed to test these hypotheses: (1) Using appropriate bioassays, the effect of CXCL7 peptides on the ME will be characterized using different forms of the peptide generated as recombinant proteins. (2) Abnormal patterns of CXCL7 expression by MDS-derived monocytes will be identified and correlated with clinical data to establish an association between abnormal expression and pathogenesis. (3) The stromal signals and subsequent molecular events responsible for the up regulation of CXCL7 gene expression in normal monocytes will be identified. This will allow for eventual delineation of mechanisms responsible for aberrant expression in MDS monocytes. Data from these studies should contribute to a precise understanding of the consequences of normal and MDS monocyte interactions within the ME, which in turn should lead to the development of novel interventions
