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

摘要 该提案概述了瑞安·M·奥康奈尔博士、 首先是两年的辅导期，最后是三年的独立研究 在获得学术机构的终身教职后。首席调查员 (P.I.)在过去的三年里，作为博士后学者，我在 大卫·巴尔的摩博士，加州理工学院，在那里有重要的研究 在miRNAs和免疫系统领域已经取得了进展。在接受指导的过程中 在拟议项目的阶段，私家侦探将继续在巴尔的摩博士的实验室工作， 在对开展拟议研究很重要的特定领域获得额外指导 议程。下一步，拟议的工作将在独立期间完成。整体而言 这项提议的科学目标是了解哺乳动物的造血是如何通过 炎性应激过程中的microRNA。这一研究方向得到了令人瞩目的支持 初步数据，以及压倒性的医学需要了解造血应激 导致癌症、贫血、免疫缺陷和自身免疫等疾病。私家侦探。 之前已经发现了一种特定的microRNA，miR-155，它是在造血系统中诱导的 系统在炎症期间，并足以引起骨髓增殖性疾病在其 在造血系统中持续表达。因此，中心假设是 测试的是生理调节的miR-155是否在 炎症，并通过直接抑制SHIP1和选择特定的C/EBP蛋白来实现 待表达的异构体。结果将决定miRNAs是否调节造血 在生理上相关的炎症应激过程中，并为此提供了机制基础 功能。此外，还将获得关于miRNAs如何作为 炎症和血液疾病之间的联系。

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.