MICRO RNA TARGETING OF NORMAL & LEUKEMIA STEM- PROGENITOR CELLS

正常的 MICRO RNA 靶向

• 批准号: 8212935
• 负责人: CURT I CIVIN
• 金额: $ 31.13万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8212935
• 关键词: 3' Untranslated Regions; Acute Myelocytic Leukemia; Affect; Allogenic; Antigen-Presenting Cells; Apoptosis; Applications Grants; Base Pairing; Binding; Blood; Bone Marrow Transplantation; CD34 gene; CD95 Antigens; Cancer Patient; Cell physiology; Cells; Clinical; Clinical Pathways; Clinical Trials; Complication; Comprehensive Cancer Center; Data; Databases; Development; Development Plans; Erythroid; Erythropoiesis; Failure; Funding; Genes; Hematologic Neoplasms; Hematopoiesis; Hematopoietic; Hematopoietic Stem Cell Transplantation; Human; Immunocompromised Host; In Vitro; Incubated; Individual; Informatics; Laboratories; Lead; Left; Leukemic Hematopoietic Stem Cell; Longitudinal Studies; Marrow; Messenger RNA; MicroRNAs; Modeling; Molecular; Mus; Myelogenous; Play; Predisposition; Premalignant; Process; Progress Reports; Proteins; Publishing; Recombinants; Regulation; Resistance; Resources; Role; Site; Specific qualifier value; Staging; Stem cells; T-Lymphocyte; Technology; Translational Research; Translations; Transplant Recipients; Tumor Necrosis Factor Ligand Superfamily Member 6; base; cancer stem cell; effective therapy; graft vs host disease; improved; killings; leukemia; leukemic stem cell; leukemogenesis; mRNA Expression; member; novel; prevent; progenitor; research study; scale up; stem; stem cell biology; translational approach; translational study

Project 4: MicroRNA targeting of normal and leukemia stem-progenitor cells (Civin) MicroRNAs bind to 3' untranslated region sites in target mRNAs to down-regulate translation to protein. Since microRNAs do not base-pair exactly with their target mRNAs, they can block protein translation of many mRNAs and serve as powerful switches to regulate cell functions. To extend our long-term studies on regulation of hematopoiesis and stem cell biology, we profiled microRNA expression in hematopoietic stemprogenitor cells (HSPCs). We combined this data with human HSPC mRNA expression results and microRNA-mRNA target predictions into a novel database which predicted that certain of the HSPCexpressed microRNAs (HE-microRNAs) targeted several mRNAs critical to hematopoiesis. On this informatic basis, we formulated a model for microRNA control of hematopoiesis in which many genes specifying hematopoietic differentiation are expressed by early HSPCs, but held in check by HE-microRNAs. For several target mRNAs, we then demonstrated experimentally that translation is actually decreased by microRNAs. Mir-155 potently reduced myeloid and erythroid colony formation of normal human HSPCs, and mir-16 selectively inhibited erythropoiesis. Since the cells that we studied include rare stem cells and various stages of progenitors, we propose in Aim 1, to expand our microRNA profiles of HSPCs to more highly purified subsets of primary human and mouse HSPCs and primary human acute myeloid leukemia (AMI) cells. In Aim 2, we will determine if selected individual microRNAs experimentally inhibit development of primary HSPCs, as our model predicts, and if these microRNAs affect AMI stem cells and leukemogenesis. We will determine the proteins whose synthesis is inhibited by each functionally-active microRNA and thereby the molecular mechanisms of the hematopoietic effects. At this point in our studies, at least 2 of these microRNAs, mir-16 and mir-155 appear to be new regulators of normal hematopoietic and cancer stem cells. Relevance: We suggest that a major barrier impeding cure of the many cancer patients whom we cannot cure today is our failure to effectively attack and eliminate cancer stem cells. Specifically, we believe that development of more effective therapies in leukemia hinges on fuller understanding of the regulation of rare normal and leukemic hematopoietic stem cells. The studies in this project investigate the effects of new regulatory molecules called microRNAs, which appear to play previously unexpected, potent roles in control of blood formation and leukemia. Understanding the actions of these hematopoietic-regulatory microRNAs may provide new targets, for both expansion of normal stem cells and leukemia therapy.

项目4：靶向正常和白血病干细胞（CIVIN）的microRNA靶向 MicroRNA与靶mRNA中的3'未翻译区域结合，以下调转化为蛋白质。 由于microRNA不能与目标mRNA完全碱基对，因此它们可以阻止 许多mRNA并用作调节细胞功能的强大开关。扩展我们对有关的长期研究 调节造血和干细胞生物学，我们在造血干性干燥剂中介绍了microRNA的表达 细胞（HSPC）。我们将这些数据与人类HSPC mRNA表达结果相结合，并 MicroRNA-MRNA目标预测到一个新的数据库中，该数据库预测了某些HSPCEXPESSEDSEDS MicroRNA（He-Micrornas）针对的几个对造血至关重要的mRNA。关于这个信息 基础，我们为造血的microRNA控制制定了一个模型，其中许多基因指定了 造血分化由早期的HSPC表示，但由He-Micrornas检查。为了 几个目标mRNA，然后我们通过实验证明了翻译实际上通过 microRNA。 miR-155有效降低了正常人HSPC的髓样和红系菌落的形成，以及 miR-16选择性抑制红细胞生成。 由于我们研究的细胞包括罕见的干细胞和祖细胞的各个阶段，因此我们建议 AIM 1，将HSPC的microRNA概况扩展到更高度纯化的原代人的子集和 小鼠HSPC和原发性人类急性髓样白血病（AMI）细胞。在AIM 2中，我们将确定是否 正如我们的模型所预测的那样 如果这些microRNA会影响AMI干细胞和白血病。我们将确定其蛋白质 每个功能活性microRNA抑制合成，从而抑制了合成的分子机制 造血作用。在我们的研究中，至少有2个MicroRNA，miR-16和miR-155出现 是正常造血和癌症干细胞的新调节剂。 相关性：我们建议，阻碍许多我们无法治愈的主要障碍，我们无法治愈许多癌症患者 今天的治疗是我们无法有效攻击和消除癌症干细胞。特别是，我们相信 在白血病中开发更有效的疗法取决于对罕见的调节的全面了解 正常和白血病造血干细胞。该项目的研究调查了新的影响 称为microRNA的调节分子，在控制中似乎起着出乎意料的有效作用 血液形成和白血病。了解这些造血调节性microRNA的作用 可以为正常干细胞和白血病疗法的扩展提供新的靶标。