权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Mdm2 Alternative Splicing in DNA Damage and Cancer

Mdm2 选择性剪接在 DNA 损伤和癌症中的作用

基本信息

批准号：
10738347
负责人：
Dawn S Chandler
金额：
$ 6.53万
依托单位：
RESEARCH INST NATIONWIDE CHILDREN'S HOSP
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10738347
关键词：
Adult Alanine Transaminase Alternative Splicing Antineoplastic Agents Astrocytoma Automobile Driving Binding Binding Proteins Bioinformatics Biological Assay Biology Biophysics Breast Cancer Biology Cell Line Cell Proliferation Cells Cellular Stress Chemistry Childhood Glioma Complex Coupled DNA Damage Data Disease Dominant-Negative Mutation Engineering Event Excision Exons Future Generations Genes Genetically Engineered Mouse Genome Genotoxic Stress Glioma Goals High-Throughput Nucleotide Sequencing Human In Vitro Knowledge Length Lung Lymphoma MDM2 gene Malignant Childhood Neoplasm Malignant Neoplasms Measures Mechanics Mediating Methodology Methods MicroRNAs Modality Modeling Molecular Mus Mutation Nuclear Nuclear Protein Nuclear RNA Oligonucleotides Oncogenic Outcome Ovary Pathway interactions Pharmacologic Substance Phenotype Play Positioning Attribute Primary Neoplasm Property Protein Isoforms Proteins Publishing RNA RNA Biochemistry RNA Processing RNA Sequences RNA Splicing RNA metabolism RNA-Binding Proteins Regulation Regulatory Element Repression Research Rhabdomyosarcoma Role Sampling Stress System TP53 gene Technology Testing Therapeutic Therapeutic Intervention Tumor Suppressor Proteins Variant Viral Work Xenograft procedure cancer therapy cancer type cell growth cell type chemotherapeutic agent combinatorial design drug discovery exon skipping genotoxicity industry partner liposarcoma mRNA Precursor mouse model novel novel therapeutic intervention overexpression prevent response therapy design tumor tumor progression tumorigenesis tumorigenic

项目摘要

ABSTRACT Tumor suppressor p53 is the quintessential guardian of the genome whose function is inhibited in greater than 50% of all human cancers. Though mutation and deletion of p53 are major contributors to p53 inactivation, overexpression of the negative regulators MDM2 and MDM4 (MDMX) are also known to inactivate p53, thus leading to the cancer phenotype. Our lab has shown that specific types of cell stress initiate the generation of an alternatively spliced isoform of MDM2. The predominant MDM2 alternative isoform, MDM2-ALT1 also known as MDM2-B, functions to primarily activate the p53 pathway by inhibiting MDM2 and MDM4 in a dominant negative fashion. Paradoxically, this isoform is upregulated in several human cancers, such as pediatric high-grade gliomas, astrocytomas, rhabdomyosarcomas (RMS), and liposarcomas, as well as adult cancers such as lymphomas and those of the breast. Thus, MDM2-ALT1 plays opposing roles in cancer progression dependent upon the context of its expression. In the proposed research, we will study the underpinnings of the control of the p53 pathway by MDM2-ALT1 to better understand 1) the specific mechanism by which that MDM2-ALT1 is generated in cancer and 2) the ability of the resultant isoforms to be targeted using splice-switching oligonucleotides. We hypothesize that the expression of oncogenic MDM2- ALT1 is modulated by alterations in protein and RNA nuclear factors during the progression to tumorigenesis and can be targeted to induce splicing changes. We will use assays that identify and measure splice regulation in conjunction with gene editing approaches to identify RNA sequences and their respective nuclear factor- binding partners necessary for regulation of MDM2 splicing. Furthermore, we will use novel genetically engineered mouse models as well as established mouse xenograft assays and novel splice switching oligonucleotides (SSOs) to modulate MDM2 isoform levels. Our work will broaden our knowledge of combinatorial regulation of RNA processing in response to stress and in cancer and interrogate the utility of MDM2 isoforms modulation for rational control of the p53 pathway.

摘要抑癌基因P53是基因组的典型守护者，其功能被抑制的程度超过占所有人类癌症的50%。虽然P53的突变和缺失是P53失活的主要原因，负调控基因MDM2和MDM4(MDMX)的过度表达也可以使P53失活，因此导致癌症表型。我们的实验室已经表明，特定类型的细胞应激启动了 MDM2的另一种剪接异构体。主要的MDM2替代亚型MDM2-ALT1还被称为MDM2-B的作用主要是通过抑制MDM2和MDM4激活P53通路。占主导地位的负面时尚。矛盾的是，这种异构体在几种人类癌症中表达上调，例如儿童高级别胶质瘤、星形细胞瘤、横纹肌肉瘤和脂肪肉瘤，以及成人淋巴瘤和乳腺癌等癌症。因此，MDM2-ALT1在癌症中扮演相反的角色行进取决于其表达的上下文。在建议的研究中，我们会研究 MDM2-ALT1控制P53通路的基础以更好地理解1)特异性 MDM2-ALT1在癌症中产生机制和2)生成的异构体的能力靶向使用剪接开关寡核苷酸。我们假设致癌MDM2的表达- ALT1在肿瘤发生过程中受蛋白质和RNA核因子变化的调节并且可以被靶向地诱导剪接变化。我们将使用识别和测量剪接调控的分析方法结合基因编辑方法来识别RNA序列及其各自的核因子- MDM2剪接调控所需的结合伙伴。此外，我们将从基因上使用小说工程小鼠模型以及已建立的小鼠异种移植试验和新的剪接切换调节MDM2亚型水平的寡核苷酸(SSO)。我们的工作将拓宽我们对 RNA加工在应激反应和癌症中的组合调节，并询问 MDM2异构体调控P53通路的合理调控。