Long Nuclear-Retained Non-Coding RNAs and Cancer

长核保留非编码 RNA 与癌症

• 批准号: 8234412
• 负责人: DAVID L SPECTOR
• 金额: $ 43.22万
• 依托单位: COLD SPRING HARBOR LABORATORY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8234412
• 关键词: Address; Alleles; Alternative Splicing; Biochemical; Biological; Breast; Breast Cancer Model; Cancer Biology; Cells; Chromatin; Code; Complex; Development; Diagnostic; Disease; Embryo; Etiology; Eukaryota; Exhibits; Fibroblasts; Functional RNA; Future; Gene Expression; Genes; Genetic Transcription; Genome; Genomics; Goals; Human; Human Genome; Instruction; Knock-out; Knockout Mice; Laboratories; Lead; Liver; Lung; Malignant Neoplasms; Mammary Neoplasms; Modeling; Molecular; Mus; NCI Center for Cancer Research; Neoplasm Metastasis; Neoplasm Transplantation; Nonmetastatic; Nuclear; Nucleic Acid Regulatory Sequences; Organism; Outcome; Pathway interactions; Pattern; Play; Polycomb; Property; Prostate; Proteins; Proteome; RNA; RNA Sequence Analysis; RNA Splicing; Ribonucleoproteins; Role; Sampling; Series; Site; Spliced Genes; Tetanus Helper Peptide; Tissue-Specific Gene Expression; Tissues; Transcript; Transgenic Organisms; Vision; cancer initiation; cancer therapy; cell type; gain of function; genome sequencing; human disease; in vivo; innovation; insight; interest; loss of function; mRNA Precursor; malignant breast neoplasm; mammary gland development; mouse development; mouse genome; mouse model; next generation; overexpression; therapeutic target; tumor; tumor progression; tumorigenesis

Project 3: D. Spector Long Nuclear-Retained Non-Coding RNAs and Cancer Hannon, Gregory J PROJECT SUMMARY (See instructions): Long nuclear retained non-coding RNAs (IncRNAs) represent a large and relafively unmined class of RNAs that are likely to play critical roles in gene regulafion and disease etiology. A major challenge is to understand the molecular functions of specific IncRNAs both at the cellular level and within the context of an organism. The long-term goal of this project is to identify and characterize IncRNAs that play a critical role in mammary gland development and the inifiation and progression of breast cancer. Here, a series of Aims are presented to dissect out the role of Malati, an abundant IncRNA localized to nuclear speckles and focally amplified in a significant number of metastatic breast cancers. Studies are proposed to develop innovative loss-of-function and gain-of-function mouse models combined with cell biological approaches to assess the function of Malati in normal development and in breast cancer initiation and metastasis. The impact of alterations in the level of Malati on tissue organization will be examined, and its effect on alternative splicing in a tissue-specific manner will be pursued by next-generation RNA-sequencing analyses. Complementary cell biological studies will delve into the role that Malati plays in nuclear organization and its impact on the dynamics of pre-mRNA splicing factors enriched in nuclear speckles. The Malati RNP will be purified using an RNA-tagging strategy and its proteome will be characterized in order to idenfify proteins responsible for its nuclear retention and to provide additional insight into its function. In the final Aim a series of newly identified IncRNAs, that are misregulated in breast cancer, will be prioritized and several will be selected for functional analyses, to identify genes and pathways that they target, and to elucidate the mechanisms by which they contribute to breast cancer tumorigenesis. Together, the proposed studies will provide important insights into the role of several IncRNAs in normal development and cancer and will lead to new opportunities for the identification and characterizafion of a new and excifing class of potential therapeutic targets.

项目 3：D. Spector 长核保留非编码 RNA 与癌症 Hannon，Gregory J 项目摘要（参见说明）： 长核保留非编码 RNA (IncRNA) 代表了一类大型且相对未被挖掘的 RNA，它们可能在基因调控和疾病病因学中发挥关键作用。一个主要的挑战是在细胞水平和生物体背景下了解特定 IncRNA 的分子功能。该项目的长期目标是识别和表征在乳腺发育以及乳腺癌发生和进展中发挥关键作用的 IncRNA。在此，提出了一系列目标来剖析 Malati 的作用，Malati 是一种丰富的 IncRNA，位于核斑点中，并在大量转移性乳腺癌中局部扩增。建议研究开发创新的功能丧失和功能获得小鼠模型，并结合细胞生物学方法来评估 Malati 在正常发育以及乳腺癌发生和转移中的功能。将检查 Malati 水平的改变对组织组织的影响，并将通过下一代 RNA 测序分析来探究其对组织特异性方式的选择性剪接的影响。补充细胞生物学研究将深入探讨 Malati 在核组织中所扮演的角色及其对细胞核组织的影响。 核斑点中富集的前 mRNA 剪接因子的动态。 Malati RNP 将使用 RNA 标记策略进行纯化，并将对其蛋白质组进行表征，以鉴定负责其核保留的蛋白质并提供对其功能的更多了解。在最终目标中，将优先考虑一系列新发现的在乳腺癌中失调的 IncRNA，并选择其中一些进行功能分析，以确定它们靶向的基因和途径，并阐明它们促进乳腺癌肿瘤发生的机制。总之，拟议的研究将为了解几种 IncRNA 在正常发育和癌症中的作用提供重要见解，并将为鉴定和表征一类新的令人兴奋的潜在治疗靶点带来新的机会。