AREA IV IMMUNOLOGY

IV 区免疫学

• 批准号: 8357150
• 负责人: MARK PEZZANO
• 金额: $ 37.02万
• 依托单位: CITY COLLEGE OF NEW YORK
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-21 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8357150
• 关键词: Affinity; Area; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; Biology; Boston; Cell Communication; Cell Line; Cells; Collaborations; Complex; Development; Doctor of Philosophy; Drosophila genus; Epigenetic Process; Erythrocytes; Erythroid Cells; Faculty; Funding; GFI1B gene; Gene Targeting; Genes; Goals; Grant; Growth Factor; Hematopoietic; Histones; Human; Immune; Immune system; Immunologist; Immunology; Interest Group; Laboratories; Manuscripts; Medicine; Memorial Sloan-Kettering Cancer Center; Methylation; Microbiology; Molecular; Mus; Myelogenous; N-terminal; National Center for Research Resources; New York; Pediatric Hospitals; Positioning Attribute; Postdoctoral Fellow; Principal Investigator; Proteins; RNA Interference; Recruitment Activity; Regulation; Research; Research Infrastructure; Research Personnel; Research Project Grants; Resources; Role; Route; Source; Subgroup; Systemic Lupus Erythematosus; Systems Development; T-Lymphocyte; Transcription Repressor/Corepressor; Transcriptional Regulation; United States National Institutes of Health; Work; base; college; cost; falls; gene repression; graduate student; human GFI1B protein; link protein; medical schools; member; neutrophil; programs; protein complex; research and development

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.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 第四区域免疫学的目标是了解控制免疫系统发育和功能的细胞与细胞相互作用和分子机制。 在该组中，一个较小的亚组专注于在发育和调节水平上调节自身免疫的机制。 第四区有六名成员，包括来自纽约市立大学医学院微生物学和免疫学系的2名研究活跃的教师和来自生物学系的4名教师。 William Boto、Shubha Govind和Jerry Guyden是通过RCMI赠款直接聘用的。Mark Pezzano在担任RCMI项目副主任并与Guyden博士合作研究项目数年后，被招聘为生物系的教师职位。 Paul Gottlieb和琳达Spatz被纽约市立大学医学院聘用，并被招募加入RCMI计划，因为他们在我们上次提案中发起免疫学小组时，积极开展了专注于自身免疫的研究合作。 所有这些研究人员目前都有外部资金支持他们的研究项目，许多人在小组内部和外部研究人员都有合作项目。 该小组的研究兴趣是多样化的，从果蝇的先天免疫系统发育和功能的研究到人类的SLE。 我们有几个研究人员研究B和T细胞中免疫细胞发育和免疫系统调节的各个方面，这些方面集中在免疫学中的一个关键问题上，即免疫系统如何区分自我和非自我。 这些研究与自身免疫性疾病的发展直接相关。 在这段时间里，我们申请资金聘请一名额外的免疫学家，以增加我们在这一令人兴奋的研究领域的临界质量。 2008年秋天，来自纪念斯隆-凯特琳癌症中心马尔科姆-摩尔博士实验室的希琳-萨莱克加入了免疫学小组（第四区）。 Shireen获得了博士学位。来自纽约的爱因斯坦医学院。 她曾是斯图尔特·H. Orkin在波士顿儿童医院和哈佛医学院。作为一名研究生，她研究了IgH基因位点的转录调控。她的主要工作总结在两篇第一作者的《免疫学杂志》手稿中。 作为一名博士后研究员，她从事转录抑制因子（称为Gfi（生长因子独立性）蛋白）在造血谱系决定和分化中的作用。她首先专注于Gfi-1b基因，并通过基因靶向显示其表达对小鼠红细胞和巨核细胞发育至关重要。以此为背景，她接着询问Gfi-1b及其相关蛋白Gfi-1（在骨髓分化中至关重要）如何起作用。为此，她在红细胞系中亲和标记了Gfi-1b，并纯化了蛋白质复合物用于微测序。 通过这一途径，她发现Gfi蛋白的共享N-末端SNAG结构域招募了一个转录辅阻遏物复合物，包括CoREST和组蛋白脱甲基酶LSD-1。使用RNAi，她表明CoREST和LSD-1对于三种不同谱系（红细胞，巨核细胞和中性粒细胞）的正确分化至关重要，LSD-1的丢失与Gfi-1b靶基因H3 K4甲基化增加有关。通过这种方式，她闭合了环，揭示了Gfi蛋白如何将造血细胞中的转录抑制和表观遗传调控联系起来。