The basic thesis of this proposal is that Hox homeobox genes are important regulators of normal hematopoiesis. This application will test two hypotheses; 1) that blood cell differentiation is regulated by the orchestrated deployment of specific Hox genes; 2) that Hox proteins regulate gene transcription by binding DNA as heterodimers with other partners including Pbx; and 3) that retinoids and their receptors are key regulators of Hox expression. In order to test these hypotheses, Dr. Lawrence proposes four specific objectives. The first specific aim will further characterize hematologic defects in HoxA9 null mice. This will include transplant studies to delineate stem cell defects; a survey of adhesion molecule expression and a study of the effects of other homeobox mutations on the HoxA9 null phenotype. The second specific aim will attempt to identify direct target genes for Hox genes in blood cells. A Tet-inducible system will be used to express HoxA9 in a novel HoxA9 null cell line using a cDNA array to analyze differential gene expression. The third specific aim will characterize the hematopoietic consequences of compound homeobox gene mutations. The consequences of mutants involving members of the same Hox paralog or members of the same cluster will be analyzed. The fourth specific aim will characterize the role of retinoids and their receptors as regulators of Hox genes in blood cells. This will involve a) analysis of Hox gene activation in hematopoietic precursors by retinoic acid and b) assessing responses of specific Hox deficient blood cells to retinoids.
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