Identifying a network of microRNAs and genes that regulate breast tumor metastasi

识别调节乳腺肿瘤转移的 microRNA 和基因网络

基本信息

批准号：
8300449
负责人：
Huiping Liu
金额：
$ 13.37万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-19 至 2013-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8300449
关键词：
Algorithms BRCA1 gene Biological Assay Biological Markers Bioluminescence Biomedical Engineering Blood Circulation Breast Breast Cancer Cell Breast Cancer Model Bypass Cancer Patient Cancer cell line Cause of Death Cell physiology Cells Chemistry Chicago Chromatin Clinical Clinical Medicine Correlation Studies Data Detection Drug Compounding Drug resistance EZH2 gene Electrophoretic Mobility Shift Assay Epithelial Family Fatty acid glycerol esters Future Gene Targeting Genes Genetic Goals Human Image In Vitro Knowledge Length Lentivirus Vector Luciferases Lung Malignant Neoplasms Mammary Neoplasms Mammary gland Medicine Mentors Mesenchymal Messenger RNA MicroRNAs Microarray Analysis Modeling Molecular Monitor Mus Mutation Neoplasm Metastasis Nucleotides Optical reporter Patients Phase Property Protocols documentation Regulation Reporting Research Personnel Research Training Resistance Small RNA Specimen Stem cells Technology Therapeutic Toxic effect Transcriptional Regulation Translating Transplantation Tumor-Derived United States Universities Western Blotting Xenograft Model base breast cancer diagnosis cancer cell cancer initiation cancer therapy clinical application improved in vivo innovation lymph nodes malignant breast neoplasm mortality neoplastic cell novel overexpression post-doctoral training pre-clinical preclinical study prevent promoter therapeutic target tumor tumor growth tumor initiation tumor progression

项目摘要

DESCRIPTION (provided by applicant): Metastasis is the major cause of death in breast cancer patients. However, the molecular mechanisms underlying tumor initiation and metastasis are not clear. We have recently identified tumor initiation cells (TICs) from human breast tumors. TICs carry certain properties of stem cells, are more resistant to conventional cancer therapies, and are involved in tumor metastasis. How to effectively target TICs or metastasis initiating cells (MICs) thus becomes one of the most propelling questions. Endogenous single strand small RNAs of 20- 22 nucleotides in length, known as microRNAs (miRNAs, miRs), have emerged to be powerful regulators of tumor progression. In this project, we aim to characterize novel miRs that regulate human breast cancer initiation and metastasis and identify their target genes. Then in our future endeavors, we will examine miR regulation mechanisms at the transcriptional level and further translate our understanding to clinical applications, such as novel cancer biomarkers or therapeutics. Most previous metastasis models are limited in their ability to fully represent human tumors, due to genetic changes accumulated in culture for human cancer cell lines, genetic differences in mouse tumor models compared to human tumors, and bypassing the natural steps of metastasis via bloodstream inoculations. This project will take advantage of our recently established human-in-mouse breast cancer models, which are derived from clinical tumor specimens and develop spontaneous lung or lymph node metastases upon orthotopic transplantation into mouse mammary fat pads. To closely monitor breast tumor initiation and metastasis in vivo, we have also transduced primary cancer cells with optical reporters and improved the detection sensitivity to 10 cells in vivo via non-invasive bioluminescence imaging. MiRs are more stable and resistant to analysis protocols than mRNAs, thus serving as promising novel cancer biomarkers. Furthermore, they are endogenous small RNAs with little toxicity compared to compound drugs; therefore hold the promise to be developed as innovative cancer therapeutics. Our long-term goal is to combine our understanding of tumor initiation and metastasis with knowledge in multi- disciplinary technology (such as chemistry and bioengineering) to improve clinical medicine and reduce cancer mortality. PUBLIC HEALTH RELEVANCE: Using patient tumor-derived human breast cancer models, this project aims to identify a novel network of microRNAs and their target genes critical for breast cancer initiation and/or metastasis. Newly identified microRNAs are promising candidates for novel biomarkers and therapeutics for cancer medicine. I am a permanent resident in the United States. I am in my 5th year of postdoctoral training at The University of Chicago, and am ready to make a timely transition to an independent investigator upon completing the one-year mentored phase. This application proposes a 1-year mentored phase (100% effort) and a 3-year independent phase (80% effort) to complete the research and training goals.

描述（由申请人提供）：转移是乳腺癌患者死亡的主要原因。但是，尚不清楚肿瘤起始和转移的分子机制。我们最近从人乳腺肿瘤中鉴定出肿瘤起始细胞（TICS）。 TIC具有某些干细胞的特性，对常规癌症疗法具有更耐药性，并且参与肿瘤转移。如何有效靶向抽动或转移引发细胞（麦克风）因此成为最具推动性的问题之一。长度为20-22个核苷酸的内源性单链小RNA，称为microRNA（miRNA，mirs），已成为肿瘤进展的强大调节剂。在这个项目中，我们旨在表征调节人类乳腺癌开始和转移并识别其靶基因的新型MIR。然后，在我们未来的努力中，我们将在转录水平上检查miR调节机制，并将我们的理解进一步转化为临床应用，例如新型的癌症生物标志物或治疗剂。大多数以前的转移模型的完全代表人类肿瘤的能力受到限制，这是由于人类癌细胞系中培养中积累的遗传变化，与人类肿瘤相比，小鼠肿瘤模型的遗传差异，并通过血液接种绕过转移的天然步骤。该项目将利用我们最近建立的人类乳腺癌模型，这些模型是从临床肿瘤标本中得出的，并在正常移植到小鼠乳腺脂肪垫上的原位移植后发展自发肺或淋巴结转移。为了密切监测体内乳腺肿瘤的启动和转移，我们还通过光学记者转导了原代癌细胞，并通过非侵入性生物发光成像提高了对10个细胞的检测敏感性。与mRNA相比，miR对分析方案更稳定，对分析方案具有抵抗力，因此是有前途的新型癌症生物标志物。此外，与复合药物相比，它们是内源性的小RNA，毒性很小。因此，承诺将作为创新的癌症治疗剂发展。我们的长期目标是将我们对肿瘤起始和转移的理解与多学科技术（例如化学和生物工程）的知识相结合，以改善临床医学并降低癌症死亡率。公共卫生相关性：使用患者肿瘤衍生的人类乳腺癌模型，该项目旨在确定一个新颖的microRNA网络及其对乳腺癌启动和/或转移至关重要的靶基因。新确定的microRNA是新型生物标志物和癌症医学治疗剂的有前途的候选者。我是美国的永久居民。我正在芝加哥大学接受博士后培训的第五年，并准备在完成为期一年的指导阶段后及时向独立的调查员过渡。该申请提出了为期1年的指导阶段（100％的努力）和3年独立阶段（80％的努力）来完成研究和培训目标。