This career development proposal is designed to provide training and support for the applicant to become an independent physician-scientist, who is focused on the regulation of hematopoietic self-renewal and differentiation by the retinoid receptors. The goals of this proposal are to obtain practical and didactic training in scientific methodology, technical skills, grant writing and scientific publication. Retinoids regulate the opposing pathways of hematopoietic self-renewal and differentiation. Retinoids bind to six distinct cognate retinoid receptors, altering the transcriptional activity of these nuclear receptors from transcriptional repressors to transcriptional activators. Retinoid receptors RAR? and RAR? have been implicated in programs of hematopoietic differentiation and self-renewal, respectively. In addition, acute promyelocytic leukemia is associated with the recurrent t(15;17) translocation, which creates two fusion proteins (PML-RAR? and RAR?-PML), and haploinsufficiency for both RAR? and PML. The role of RAR? haploinsufficiency in early leukemic dysregulation by t(15;17) has not been defined and the distribution of natural retinoids that regulate retinoid-receptor dependent programs of self-renewal and differentiation, has not been assessed. In this project we will define the role of RAR? haploinsufficiency on the early dysregulation of hematopoietic self-renewal using RAR? deficient mice bred with our well characterized model of acute promyelocytic leukemia, the mCG-PR mouse. We will also generate a new UAS/Gal4 reporter mouse and assess the distribution of natural RAR?, RAR? and RXR? activating retinoids across hematopoietic compartments. These studies will determine: 1). The role of RAR? haploinsufficiency in acute promyelocytic leukemia;2). The spatial-temporal distribution of natural retinoid ligands during hematopoiesis;3). Whether opposing pathways of self-renewal and differentiation are regulated by distinct receptor specific retinoids or by regulation of functional retinoid receptor availability;4). Whether physiologic or pathologic stimuli alter hematopoiesis by regulating the production and distribution of retinoids.
The goal of this proposal is to train an independent physician-scientist for a career focused on normal and leukemic production of white blood cells. The proposed research plans to define the role of retinoids and retinoid receptors in regulating hematopoietic self-renewal and differentiation.
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