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

基本信息

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
项目类别：
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

项目摘要

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）：拟议的研究旨在调查长非编码 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，可感知和修复 DNA 损伤以维持基因组完整性，其中 lncRNA（一类新型调节 RNA 分子）可能发挥重要作用。在这项拟议的研究中，我发现了强有力的证据表明 lncRNA 受到 ATM（DDR 中的一种重要激酶）的调节。其中两种 lncRNA，称为 JANDA（Jade1 相关 ncRNA DNA 损伤激活）和 MANDS（Mfhas1 相关 ncRNA DNA 损伤抑制），对染色质重塑和乳腺肿瘤发生和转移具有显着影响。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 Mfhas1（一种候选癌基因之外的 ROCO 蛋白）作为肿瘤抑制剂，JANDA 的失调可能有助于乳腺肿瘤的进展和转移。在目标1中，我将探讨JANDA和MANDS在DDR中的分子机制。我还将确定 JANDA 和 MANDS 对基因表达的全局调控及其在 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度表达，并且可能在乳腺癌发生过程中具有促癌特性，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致癌应激的反应细胞。 JANDA 可能作为一种新的负面预后因素，并在 HER2 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 对曲妥珠单抗耐药的影响HER2 型肿瘤。最后，我将评估 JANDA 作为乳腺癌的潜在治疗靶点。这项拟议的研究将为我提供在学术界开始独立职业生涯的最佳机会。我的长期目标是探索非编码 RNA 对健康和疾病的贡献。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。对于我的职业发展，我将学习提高管理实验室、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长期以来一直是转化癌症研究领域的领导者，我能够将最先进的研究转化为临床应用。在 K99/R00 的支持下，我将能够 1) 完成拟议的研究并探索初步研究中产生的新想法，2) 寻找在化疗和放疗中使人类乳腺癌细胞敏感的新策略，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。