Characterization of long non-coding RNAs in the DNA damage response

DNA 损伤反应中长非编码 RNA 的表征

• 批准号: 8748791
• 负责人: Guohui Wan
• 金额: $ 9.85万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-09 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8748791
• 关键词: Academia; Acetylation; Apoptosis; Arts; Binding; Biological Assay; Biology; Breast Cancer Cell; Breast Epithelial Cells; Cancer Biology; Cancer Center; Cell physiology; Cells; Collaborations; Complex; DNA Damage; DNA Repair; DNA lesion; Data; Development; Disease; ERBB2 gene; Engineering; Epigenetic Process; Eukaryotic Cell; Exhibits; Functional RNA; Gene Expression Profile; Gene Expression Regulation; Genes; Genetic Transcription; Genome; Genomic DNA; Genomics; Goals; HBO1 histone acetyltransferase; Health; Histone Deacetylase; Histone H4; Human; In Vitro; Laboratories; Learning; Link; Maintenance; Malignant Neoplasms; Mammary Neoplasms; Mammary gland; Measures; Mentors; Metastatic Neoplasm to the Breast; Molecular; Molecular Biology; Mus; Neoplasm Metastasis; Oncogenes; Oncogenic; Organism; Phosphotransferases; Play; Postdoctoral Fellow; Process; Prognostic Factor; Property; Proteins; RNA; Radiation therapy; Recording of previous events; Regulation; Research; Research Proposals; Resistance; Role; Specificity; Stem cells; Stress; Students; Therapeutic; Tissues; Transcript; Translating; Trastuzumab; Tumor Suppressor Proteins; Writing; anticancer research; breast tumorigenesis; cancer genomics; cancer initiation; career; career development; cell growth; chemotherapy; chromatin remodeling; clinical application; genome wide association study; improved; malignant breast neoplasm; mouse model; novel; novel strategies; outcome forecast; overexpression; pluripotency; promoter; response; skills; stem cell biology; therapeutic target; tumor; tumor initiation; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): The proposed study is to investigate the roles of long non-coding RNAs (lncRNAs) in the DNA damage response (DDR) and breast cancer. As a primary anti-cancer barrier in early tumorigenesis, the DDR involves a complicated and entangled network of processes that sense and repair DNA damage to maintain genomic integrity, in which lncRNAs, a novel class of regulatory RNA molecules, may play important roles. In this proposed study, I found strong evidence that lncRNAs were regulated by ATM, an essential kinase in the DDR. Two of such lncRNAs, termed JANDA (Jade1 associated ncRNA DNA damage activated) and MANDS (Mfhas1 associated ncRNA DNA damage suppressed), have significant impacts in chromatin remodeling and breast tumorigenesis and metastasis. I propose that DDR induced-JANDA is a key functional link that connects the DDR to histone H4 acetylation, and DDR suppressed-MANDS serves as a tumor suppressor by targeting Mfhas1, an ROCO protein beyond a candidate oncogene, and dysregulation of JANDA may contribute to breast tumor progression and metastasis. In Aim 1, I will explore the molecular mechanism of JANDA and MANDS in the DDR. I will also determine global regulation of gene expression by JANDA and MANDS and their roles in the DDR and DNA repair. My preliminary data showed JANDA was overexpressed in human breast tumors and may have pro-oncogenic property in breast cancer initiation, so in Aim 2 I will evaluate the expression level of JANDA and H4 acetylation in breast cancer tissues and in response to oncogenic stress in mammary cells. JANDA may serve as a novel negative prognostic factor and exhibit pro-metastatic activity in HER2 type tumors, so in Aim 3, I will assess the role of JANDA as a metastasis promoter in breast cancer and detect the effects of silencing JANDA in trastuzumab-resistant HER2 type tumors. Lastly, I will evaluate JANDA as a potential therapeutic target in breast cancer. This proposed study will provide me with the best opportunity to start up my independent career in academia. My long term goal is to explore the contribution of non-coding RNAs in health and disease. To that end, I will continue enhancing my technical skills in molecular biology, cancer biology, epigenetics, mouse engineering and manipulation, and expanding my expertise in cancer genomics, stem cell biology and translational biology. For my career development, I will learn to improve my skills on managing laboratory, mentoring postdoctoral fellows and students, scientific writing and presentation and establishing new collaborations. The Department of Cancer Biology at MD Anderson Cancer Center has a long history of being a leader in the field of translational cancer research, where I am able to translate state-of-art studies into clinical applications. With the support of K99/R00, I will be able to 1) complete the proposed studies and explore novel ideas that arise from preliminary studies, 2) search for novel strategies to sensitize human breast cancer cells in chemotherapy and radiotherapy, 3) establish my independent research team and expand my network into DNA damage, non-coding RNA and breast cancer fields.

描述（由申请人提供）：拟定的研究旨在研究长链非编码RNA（lncRNA）在DNA损伤反应（DDR）和乳腺癌中的作用。作为早期肿瘤发生中的主要抗癌屏障，DDR涉及一个复杂且纠缠的过程网络，该过程感知和修复DNA损伤以维持基因组完整性，其中一类新的调节RNA分子lncRNA可能发挥重要作用。在这项拟议的研究中，我发现了有力的证据表明lncRNA是由ATM调节的，ATM是DDR中的一种必需激酶。其中两种lncRNA，称为JANDA（Jade 1相关的ncRNA DNA损伤激活）和MANDS（Mfhas 1相关的ncRNA DNA损伤抑制），在染色质重塑和乳腺肿瘤发生和转移中具有显著影响。我认为DDR诱导的JANDA是连接DDR与组蛋白H4乙酰化的关键功能环节，DDR抑制的MANDS通过靶向候选癌基因以外的ROCO蛋白Mfhas 1作为肿瘤抑制因子，JANDA的失调可能有助于乳腺肿瘤的进展和转移。目的1：探讨JANDA和MANDS在DDR中的分子机制。我还将确定JANDA和MANDS的基因表达的全球调节及其在DDR和DNA修复中的作用。我的初步数据显示JANDA在人类乳腺肿瘤中过表达，并且可能在乳腺癌的发生中具有促癌特性，因此在目标2中，我将评估JANDA和H4乙酰化在乳腺癌组织中的表达水平以及对乳腺细胞致癌应激的反应。JANDA可能作为一种新的阴性预后因子，在HER 2型肿瘤中表现出促转移活性，因此在目标3中，我将评估JANDA作为乳腺癌转移促进剂的作用，并检测沉默JANDA在曲妥珠单抗耐药HER 2型肿瘤中的作用。最后，我将评估JANDA作为乳腺癌潜在的治疗靶点。这项拟议的研究将为我提供最好的机会，开始我在学术界的独立职业生涯。我的长期目标是探索非编码RNA在健康和疾病中的作用。为此，我将继续提高我在分子生物学，癌症生物学，表观遗传学，小鼠工程和操作方面的技术技能，并扩大我在癌症基因组学，干细胞生物学和转化生物学方面的专业知识。为了我的职业发展，我将学习提高我在管理实验室，指导博士后研究员和学生，科学写作和演示以及建立新合作方面的技能。MD安德森癌症中心的癌症生物学系在转化癌症研究领域具有悠久的历史，在那里我能够将最先进的研究转化为临床应用。在K99/R 00的支持下，我将能够1）完成拟议的研究并探索初步研究产生的新想法，2）寻找化疗和放疗中致敏人类乳腺癌细胞的新策略，3）建立我的独立研究团队并将我的网络扩展到DNA损伤，非编码RNA和乳腺癌领域。