Mechanisms of regulation by RNA in acute myeloid leukemia

RNA在急性髓系白血病中的调控机制

基本信息

批准号：
10215241
负责人：
DANIEL G TENEN
金额：
$ 104.22万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2023-07-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): This proposal, "Mechanisms of regulation by RNA in acute myeloid leukemia", is being submitted in response to PAR-14-267, "Outstanding Investigator Award (R35)", from the National Cancer Institute. The objective is to allow experienced investigators to conduct exceptional research and be more adventurous. In recent years researchers have revealed that a large portion of the genome of complex organisms are transcribed but not translated. These noncoding RNAs (ncRNAs) provide an additional and relatively unexplored layer of control to many biological processes. While many investigators are now turning to categorizing and studying ncRNAs, especially microRNAs, there are several areas which have not been extensively studied. (1) The first is the role of antisense RNAs in limiting the expression of tumor suppressor genes, especially those of master transcription factors. (2) In this era of sequencing total DNA genomes for the presence of mutations, especially in cancer, most investigators do not consider that there is another layer of modification of the genome, that of RNA editing, and that this has been shown to play a role in cancer. (3) Most importantly, many investigators are studying epigenetic modifications of the genome, especially DNA methylation, with the view that these control genome activity. Relatively little attention has been given to the potential role of RNA (i.e., transcription) in controlling epigenetic marks. The overall goal of this proposal is to investigate these 3 novel and underexplored aspects of RNA control in cancer, focusing on acute myeloid leukemia (AML) as a model for other tumor types. Therefore, this proposal will study the role of RNA biology in cancer, focusing in three novel areas: (1) the study of a noncoding RNA which limits expression of the tumor suppressor PU.1, and in particular investigate its role in the core binding factor leukemias. As time permits, other antisense RNAs will be identified. (2) The role of dysregulation of RNA editing in AML will be investigated, and in particular the suppression of the RNA editing enzyme ADAR2 in core binding factor leukemias, and the misexpression of ADAR3. (3) The ability of ncRNA to regulate epigenetic changes such as DNA methylation will be studied in more detail, with the goals of developing gene-selective demethylating tools as well as identification of other epigenetic marks regulated by ncRNAs. In addition to exploring novel areas of RNA biology, these studies will in every instance seek to investigate their role in cancer, as well as potential development of more specific therapeutic modalities, using AML as a model disease.

描述（由适用提供）：该提案是“急性髓样白血病中RNA的调节机制”，以响应国家癌症研究所的PAR-14-267，“杰出研究者奖（R35）”。目的是允许经验丰富的研究人员进行非凡的研究并更加先进。近年来，研究人员透露，复杂生物体的大部分基因组被翻译但未翻译。这些非编码RNA（NCRNA）为许多生物过程提供了额外的相对意外的控制层。尽管许多研究人员现在正在转向对NCRNA进行分类和研究，尤其是microRNA，但有几个领域尚未进行广泛研究。（1）首先是反义RNA在限制肿瘤抑制基因的表达中，尤其是主转录因子的作用。（2）在这个测序的总DNA基因组中，突变的存在，尤其是在癌症中，大多数研究者都不认为基因组的修饰层是RNA编辑的另一层，并且已经证明这在癌症中起作用。（3）最重要的是，许多研究人员正在研究基因组，尤其是DNA甲基化的表观遗传修饰，认为这些控制基因组活性。对RNA（即转录）控制表观遗传标记的潜在作用的关注很少。该提议的总体目标是调查这三本小说，癌症中RNA控制的不足方面，重点是急性髓样白血病（AML）作为其他肿瘤类型的模型。因此，该建议将研究RNA生物学在癌症中的作用，重点是三个新的领域：（1）对限制肿瘤抑制pu.1表达的非编码RNA的研究，尤其是研究了其在核心结合因子白血病中的作用。随着时间的允许，将确定其他反义RNA。（2）将研究RNA编辑功能障碍在AML中的作用，特别是抑制RNA编辑酶ADAR2在核心结合因子白血病中的作用，以及ADAR3的Misexpression。（3）将更详细地研究NCRNA调节表观遗传变化（例如DNA甲基化）（例如DNA甲基化）的能力，其目标是开发基因选择性脱甲基化工具以及鉴定由NCRNA调节的其他表观遗传标记。除了探索RNA生物学的新领域外，这些研究还将在每种情况下都旨在研究其在癌症中的作用，以及使用AML作为模型疾病的更具体的治疗方式的潜在发展。