Investigate the Role of Micro-RNA 155 in Myeloid Development during Inflammation

摘要 该提案概述了Ryan M.的5年职业发展计划。奥康奈尔博士， 从2年的指导期开始，以3年的独立研究结束 在学术机构获得终身职位后。主要研究者 （P.I.）在实验室接受了3年的博士后培训， 大卫巴尔的摩，博士，在加州理工学院， 在miRNAs和免疫系统领域已经取得了进展。在指导期间， 项目的第一阶段，P.I.将继续在巴尔的摩博士的实验室工作， 在对开展拟议研究重要的特定领域获得额外指导 施政纲要的演讲拟议的工作将在独立期间完成。整体 这项建议的科学目标是了解哺乳动物造血是如何调节的， 炎症应激中的microRNA这一研究方向得到了令人信服的支持 初步数据，以及压倒性的医疗需要，以了解造血压力如何 导致癌症、贫血、免疫缺陷和自身免疫等疾病。私家侦探 先前已经鉴定了一种特异性的microRNA，miR-155，它在造血细胞中被诱导， 系统在炎症和足以引起骨髓增生性疾病时，其 在造血系统中持续表达。因此，中心假设是 测试了生理学调节的miR-155是否促进骨髓扩增， 炎症，并通过直接抑制SHIP 1和选择特定的C/EBP？蛋白 待表达的同种型。结果将确定miRNAs是否调节造血 在生理相关的炎症应激过程中，并为此提供机制基础 功能此外，重要的见解将获得关于如何miRNA可以作为 炎症和血液病之间的联系

Abstract This proposal outlines a 5-year career development plan for Ryan M. O'Connell, Ph.D., that begins with a 2 year mentored period and finishes with 3 years of independent research upon obtaining a tenure track position at an academic institution. The principal investigator (P.I.) has undergone 3 previous years of training as a postdoctoral scholar in the laboratory of David Baltimore, Ph.D., at the California Institute of Technology where significant research progress has been made in the field of miRNAs and the immune system. During the mentored phase of the proposed project, the P.I. will continue to work in Dr. Baltimore's laboratory and receive additional guidance in specific areas important for carrying out the proposed research agenda. The proposed work will next be completed during the independent period. The overall scientific goal of this proposal is to understand how mammalian hematopoiesis is regulated by microRNAs during inflammatory stress. This research direction is supported by compelling preliminary data, and the overwhelming medical need to understand how hematopoietic stress contributes to diseases such as cancer, anemia, immunodeficiency, and autoimmunity. The P.I. has previously identified a specific microRNA, miR-155, that is induced in the hematopoietic system during inflammation and sufficient to cause a myeloproliferative disorder upon its sustained expression in the hematopoietic system. Therefore, the central hypothesis to be tested is whether physiologically regulated miR-155 promotes myeloid expansion during inflammation, and does so by directly repressing SHIP1 and selecting specific C/EBP? protein isoforms to be expressed. Results will determine whether miRNAs regulate hematopoiesis during physiologically relevant inflammatory stress, and provide a mechanistic basis for this function. Furthermore, important insights will be gained regarding how miRNAs can serve as links between inflammation and hematological disorders.