AREA IV IMMUNOLOGY

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The goal of Area IV, Immunology, is to understand the cell-to-cell interactions and molecular mechanisms that control the development and function of the immune system. Within the group, a smaller subgroup is focused on the mechanisms that regulate autoimmunity, both at the developmental and regulatory levels. There are six members of Area IV, consisting of 2 research active faculty from the CUNY Medical School department of Microbiology and Immunology and 4 from the department of Biology. William Boto, Shubha Govind and Jerry Guyden were hired through the RCMI grant directly. Mark Pezzano was recruited for a faculty position in the Biology department, after serving as Deputy Director of the RCMI program and collaborating on research projects with Dr. Guyden for several years. Paul Gottlieb and Linda Spatz were hired by the CUNY Medical School and recruited to join the RCMI program because of their active research collaboration focused on autoimmunity when the immunology subgroup was initiated in our last proposal. All of these researchers currently have outside funding for their research projects and many have collaborative projects both within the group and with outside investigators. The research interests of the group are diverse, ranging from studies of innate immune system development and function in Drosophila to SLE in humans. We have several investigators who study aspects of immune cell development in both B and T cells and immune system regulation, which are focused on a key question in Immunology as to how the immune system distinguishes self from non-self. These studies are directly relevant to the development of autoimmune diseases. In this granting period, we requested funds to hire one additional immunologist to increase our critical mass in this exciting area of research. In the Fall of 2008, Shireen Saleque from Dr. Malcolm Moore's lab at Memorial Sloan Kettering Cancer Center, joined the Immunology group (Area IV). Shireen received her PhD. from Albert Einstein College of Medicine in New York. She was a postdoctoral fellow in the laboratory of Dr. Stuart H. Orkin at Children's Hospital Boston and Harvard Medical School. As a graduate student, she studied transcriptional regulation of the IgH gene locus. Her primary work was summarized in two first-authored J. Immunology manuscripts. As a post- doctoral fellow she pursued the role of transcriptional repressors known as Gfi (growth factor independence) proteins in hematopoietic lineage decisions and differentiation. She focused first on the Gfi-1b gene and showed by gene targeting that its expression is essential for red cell and megakaryocytic development in the mouse. With this as a background she then went on to ask how Gfi-1b and its related protein Gfi-1 (which is essential in myeloid differentiation) act. To do this she affinity-tagged Gfi-1b in an erythroid cell line and purified protein complexes for microsequencing. By this route she discovered that the shared N-terminal SNAG domain of the Gfi proteins recruits a transcriptional corepressor complex including CoREST and the histone demethylase LSD-1. Using RNAi she showed that both CoREST and LSD-1 are critical for proper differentiation of three different lineages (red, megakaryocytic and neutrophil) and that loss of LSD-1 is associated with increased methylation at H3K4 at Gfi-1b target genes. In this manner she closed the loop to reveal how Gfi proteins link transcriptional repression and epigenetic regulation in hematopoietic cells.