Project 4

项目4

• 批准号: 8744320
• 负责人: Gregory J Hannon
• 金额: $ 64.73万
• 依托单位: COLD SPRING HARBOR LABORATORY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8744320
• 关键词: Basal Cell; Behavior; Biological; Biological Assay; Cell Line; Cell Maintenance; Cell Survival; Cell physiology; Cells; Characteristics; Commit; Data; Dependency; Development; Diagnosis; Disease; Distant; Engraftment; Epithelial; Epithelial Cells; Epithelium; Fatty acid glycerol esters; Female; Foundations; Gene Expression Profile; Genetic; Gland; Goals; Heterogeneity; Hormone Receptor; Human; Image; Intervention; Laboratories; Maintenance; Malignant Neoplasms; Mammary Neoplasms; Mammary Tumorigenesis; Mammary gland; MicroRNAs; Molecular Profiling; Molecular Target; Mus; Myoepithelial; NCI Center for Cancer Research; Natural regeneration; Nature; Neoplasm Metastasis; Normal Cell; Pathway interactions; Patients; Pattern; Play; Population; Pregnancy; Prevention; Property; RNA Interference; Relapse; Role; Seeds; Series; Site; Stem cells; System; Testing; Transplantation; Tumor Subtype; Woman; Work; base; cell type; in vivo; in vivo Model; innovation; killings; mRNA Expression; malignant breast neoplasm; mammary epithelium; molecular phenotype; neoplastic cell; progenitor; research study; self-renewal; stem; stem cell niche; tumor; tumor initiation; tumorigenesis; tumorigenic

Project 4 has been a leader in revealing the myriad roles played by microRNAs in human cancer. We will build upon this foundation with an increased biological focus on breast cancer. We will isolate the six, well defined mammary epithelial cell types from normal virgin and parous female mice and define their miRNA and mRNA expression profiles. In so doing, we hope to better define the mammary stem cell (MaSC) and gain an appreciation for the pathways that maintain its self-renewal. This will include a definition of miRNAs and miRNA targets that are important in the MaSC. Using normal cells as a reference point, we will work to understand the relafionship between mammary tumor initiating cells and normal mammary stem cells. In part, we aim to test the relevance of tumor initiating populations, which thus far have only been detected in transplantation studies, to breast cancer in in vivo models of basal tumorigenesis. We hope to identify pathways that determine tumor initiating potential and to relate these to self-renewal pathways used by mammary stem cells. We appreciate that both normal and tumor cells function in context, and we will therefore strive to understand how the in vivo niche supports MaSC self-renewal. Similarly, we will ask whether tumor initiating cells occupy a niche or whether their special status is a cell autonomous property. With the realization that it is usually metastatic disease that kills patients, we will also probe the niches occupied by disseminated tumor cells, which can lie dormant for decades following initial treatment before they progress to frank metastases. Using a series of highly innovative strategies, including molecular profiling, RNAi-based genetics, and sophisticated imaging a whole, this Project takes a comprehensive approach to understanding the roles of miRNAs in breast cancer.

Project 4 一直在揭示 microRNA 在人类癌症中发挥的多种作用方面处于领先地位。我们将 在此基础上，更加关注乳腺癌的生物学问题。我们将从正常处女和经产雌性小鼠中分离出六种明确的乳腺上皮细胞类型，并确定它们的 miRNA 和 mRNA 表达谱。通过这样做，我们希望更好地定义乳腺干细胞（MaSC）并了解维持其自我更新的途径。这将包括 MaSC 中重要的 miRNA 和 miRNA 靶标的定义。使用正常细胞作为参考点，我们将努力了解乳腺肿瘤起始细胞和正常乳腺干细胞之间的关系。在某种程度上，我们的目的是测试肿瘤起始群体（迄今为止仅在移植研究中检测到）与基础肿瘤发生的体内模型中的乳腺癌的相关性。我们希望找到决定肿瘤起始潜力的途径，并将这些途径与乳腺干细胞使用的自我更新途径联系起来。我们认识到正常细胞和肿瘤细胞都在环境中发挥作用，因此我们将努力了解体内生态位如何支持 MaSC 自我更新。同样，我们会问肿瘤起始细胞是否占据一个生态位，或者它们的特殊地位是否是细胞自主属性。认识到杀死患者的通常是转移性疾病，我们还将探索播散性肿瘤细胞占据的生态位，这些肿瘤细胞在初次治疗后可能会休眠数十年，然后才会进展为明显的转移。该项目采用一系列高度创新的策略，包括分子分析、基于 RNAi 的遗传学和复杂的整体成像，采用全面的方法来了解 miRNA 在乳腺癌中的作用。