Characterization of Pathways Controlling Cancer at the Level of Gene Regulation

基因调控水平上控制癌症途径的表征

• 批准号: 8865555
• 负责人: Phillip A Sharp
• 金额: $ 144.02万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-05-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8865555
• 关键词: Affect; Biology; Cancer Control; Cell Death; Cell Death Induction; Cell Differentiation process; Cell Line; Cell Nucleus; Cell Survival; Cell physiology; Cells; Collaborations; Complement; Complex; DNA Damage; Development; Developmental Process; Diagnosis; E2F1 gene; Ectopic Expression; Family; Gene Expression Profile; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Genomics; Goals; Growth; High-Throughput RNA Sequencing; Human; Instruction; Investigation; Location; Malignant Neoplasms; Mesenchymal; Mesenchymal Cell Neoplasm; Mesenchymal Stem Cells; Messenger RNA; Methods; MicroRNAs; Mus; Mutation; Normal Cell; Null Lymphocytes; Oncogenes; Pathway interactions; Phenotype; Population; Prevention; Process; Proteins; RNA; RNA Interference; Reaction; Research; Role; Shapes; Small RNA; Transcriptional Regulation; Tumor Biology; Tumor Stem Cells; Tumor Suppression; Tumor Suppressor Genes; Tumor Suppressor Proteins; Untranslated RNA; cancer cell; cancer gene expression; cancer therapy; human DICER1 protein; improved; in vivo; insight; interest; migration; mouse model; neoplastic cell; new technology; programs; promoter; protein expression; sarcoma; transcription factor; tumor; tumor growth

DESCRIPTION (provided by applicant): A major strength of the Program is the integration of changes in gene regulation with mouse models of cancer and relating these results to human cancer. The overall goals of the current Program is to investigate the roles of both short and long non-coding RNAs in the development of cancer and the importance of the Rb-E2F pathway in cell death and malignancy. miRNAs probably interact with half of all mRNAs, suppress the level of expression of most of these mRNAs by less than two fold, and yet clearly modulate the development of cancer in mouse models. These small RNAs regulate growth and cell death genes, both modulators of tumor growth, and they also shape developmental transitions. The first Overall Aim of the Program is to Investigate the effects of loss of miRNA functions on cell viability, developmental processes and the development of malignancies. The three projects are investigating the general roles of miRNAs in gene regulation including their mechanisms of action, the consequence of loss of all miRNAs in Dicer null cell lines, and the relationship between miRNAs and differentiation of mesenchymal tumors and stem cells. Targeted mouse genetics will be used to investigate the roles of miRI43-145 cluster in development and tumor suppression. This will involve exploration of the effects of activation of this family of miRNAs in tumors in vivo. The second Overall Aim is to Explore the roles of other types of non-coding RNAs in normal and malignant cells. The population of non-coding RNAs will be characterized in Dicer null and tumor cells in search of RNAi-related transcriptional regulation. This includes further investigation of possible Argonaute functions in the nucleus and the roles of non-coding RNAs generated from most promoters by divergent transcription. The large intervening non-coding RNAs (lincRNAs) regulated by p53. and their roles in tumor biology will be investigated using targeted mouse genetics. The third Overall Aim is to investigate the interactions of tumor suppressor genes Rb and p53 and non-coding RNAs in control of cancer and the plasticity of the differentiation state of cells. The relationship of line RNAs and p53 and of Rb and miRNAs in developmental transition and in maintaining cell state will be investigated. The interactions and involvement of Rb and miRNAs in induction of cell death following DNA damage will also be studied.

描述（由申请人提供）：该计划的一个主要优势是将基因调控的变化与小鼠癌症模型相结合，并将这些结果与人类癌症相关联。该项目的总体目标是研究短和长非编码RNA在癌症发展中的作用以及Rb-E2 F途径在细胞死亡和恶性肿瘤中的重要性。miRNA可能与一半的mRNA相互作用，抑制这些mRNA中的大多数的表达水平不到两倍，但在小鼠模型中明显调节癌症的发展。这些小RNA调节生长和细胞死亡基因，这两种基因都是肿瘤生长的调节因子，它们也塑造发育转变。该计划的第一个总体目标是研究miRNA功能丧失对细胞活力，发育过程和恶性肿瘤发展的影响。这三个项目正在研究miRNAs在基因调控中的一般作用，包括其作用机制，Dicer无效细胞系中所有miRNAs丢失的后果，以及miRNAs与间充质肿瘤和干细胞分化之间的关系。靶向小鼠遗传学将用于研究miRI 43 -145簇在发育和肿瘤抑制中的作用。这将涉及探索该家族的miRNAs激活对细胞凋亡的影响。 体内肿瘤第二个总体目标是探索其他类型的非编码RNA在正常和恶性细胞中的作用。非编码RNA的群体将在Dicer无效细胞和肿瘤细胞中表征，以寻找RNAi相关的转录调节。这包括进一步研究Argonaute在细胞核中可能的功能以及通过趋异转录从大多数启动子产生的非编码RNA的作用。由p53调控的大型间插非编码RNA（lincRNA）。并将使用靶向小鼠遗传学研究它们在肿瘤生物学中的作用。第三个总体目标是研究肿瘤抑制基因Rb和p53与非编码RNA在控制癌症和细胞分化状态的可塑性中的相互作用。线RNA和p53和Rb和miRNA在发育过渡和维持细胞状态的关系将被调查。Rb和miRNA在DNA损伤后诱导细胞死亡中的相互作用和参与也将被研究。