DEVELOPMENTAL BIOLOGY OF HUMAN ERYTHROPOIESIS

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PROPOSED PROGRAM (adapted from applicant's abstract) The long-term objectives of this application are to understand at a molecular and cellular level the roles of erythroid membrane proteins, hematopoietic growth factor receptors, signal transduction protein, and transcription factors during erythropoiesis. Dr. Lodish will focus on the b common chain of the IL-3/GM-CSF/IL-5 receptor and the erythropoietin receptor, respectively. Their role in erythroid differentiation will be investigated through the use of chimeric receptor constructs, receptor cytoplasmic domain fusion proteins to identify transduction proteins and their binding sites, dominant negative/positive mutants of signalling proteins such as stat and MAP kinases, assessing their function both in vitro in cell lines and fetal liver and embryonal stem (ES) cells, and in vivo in transgenic and targeted gene replacement of knock-in mice. Dr. Zon will compliment these studies by identifying novel kinases of different MAP kinase cascades and assessing their role during the development of erythroid cells. This project will also provide a bridge to Dr. Orkin's project by providing the means to define the role of three different MAP kinase cascades in transducing signals from the IL-3 and erythropoietin receptors, and in activating erythroid specific transcription factors. Dr. Orkin's project will focus on the structure-function studies of the role of GATA-1 in erythroid cells and identification of GATA factor dependent target genes critical for terminal erythroid development. Dr. Lux will study the function of ankyrin in erythroid cells through the use of targeted gene disruption and gene replacement strategies in ES cells. By these means we hope to understand more fully the process of erythropoiesis and obtain molecular insights into disorders of failure, abnormal production, or increased proliferation of erythroid cells.