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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（由申请人提供）：本提案“急性髓性白血病中RNA调控机制”是为了响应国家癌症研究所的PAR-14-267“杰出研究者奖（R35）”而提交的。其目的是让有经验的调查人员进行特殊的研究，并更具冒险精神。近年来，研究人员发现，复杂生物体的大部分基因组被转录，但不被翻译。这些非编码RNA（ncRNA）为许多生物过程提供了额外的和相对未开发的控制层。虽然许多研究人员现在转向分类和研究ncRNA，特别是microRNA，但有几个领域尚未得到广泛研究。(1)第一个是反义RNA在限制肿瘤抑制基因，特别是主转录因子表达中的作用。(2)在这个对总DNA基因组进行测序以确定突变存在的时代，特别是在癌症中，大多数研究人员不认为基因组还有另一层修饰，即RNA编辑，并且这已被证明在癌症中发挥作用。(3)最重要的是，许多研究人员正在研究基因组的表观遗传修饰，特别是DNA甲基化，认为这些控制基因组活动。相对较少关注RNA的潜在作用（即，转录）控制表观遗传标记。本提案的总体目标是调查这3种新颖和癌症中RNA控制的未充分探索的方面，专注于急性髓性白血病（AML）作为其他肿瘤类型的模型。因此，本计划将研究RNA生物学在癌症中的作用，集中在三个新领域：（1）研究限制肿瘤抑制因子PU.1表达的非编码RNA，特别是研究其在白血病核心结合因子中的作用。如果时间允许，将鉴定其他反义RNA。(2)将研究AML中RNA编辑失调的作用，特别是核心结合因子白血病中RNA编辑酶ADAR 2的抑制，以及ADAR 3的错误表达。(3)ncRNA调节表观遗传变化（如DNA甲基化）的能力将被更详细地研究，目标是开发基因选择性去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，这些研究将在每种情况下寻求研究它们在癌症中的作用，以及使用AML作为模型疾病的更具体治疗方式的潜在发展。