Detecting Cancer at the Single-Cell Level Using Endogenous Signal Biomolecular Sensors

使用内源信号生物分子传感器在单细胞水平检测癌症

• 批准号: 1105524
• 负责人: Leonidas Bleris
• 金额: $ 33.46万
• 依托单位: University of Texas at Dallas
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1105524&HistoricalAwards=false
• 关键词: Detecting; Cancer; Single; Cell; Level

Cancer is a class of cellular diseases characterized by uncontrolled growth, invasion, and metastasis. Although cancer is multifaceted with complex underlying genetic determinants, emerging evidence points to common signatures at the level of intracellular signaling across different tissue and cancer types. A system capable of detecting combinations of these intracellular molecular signals in cells has significant potential for the diagnosis, prevention, treatment, and monitoring of the disease at a single-cell level. Recently, scientists have developed first generation genetic circuits and sensors that operate as information processing systems in cells. The proposed research will develop and study molecular biosensors engineered to detect and monitor endogenous microRNAs, a class of small, noncoding RNAs that regulate gene expression by targeting RNA transcripts. The objectives of the proposed research are to: (a) design and optimize molecular biosensors that respond with sensitivity and specificity to combinations of endogenous microRNAs, (b) develop monoclonal tumor cell lines with integrated biosensors based on the NCI-60 panel, and (c) study microRNAs and their relationship to disease by monitoring their expression through the cell cycle in response to drug treatment.Intellectual merit: MicroRNAs have emerged as important modulators in both development and disease, including cancer. Experimental evidence implicates aberrant microRNA expression profiles in most human malignancies. The ability to process microRNA information reliably (with single-cell resolution) will generate new tools for basic cancer research and lead to new cancer treatment modalities. Specifically, the application of the microRNA biosensors to tumor cell lines will dramatically advance our understanding of microRNA expression and dynamics in living cells. The development of monoclonal cell lines with the selected microRNA sensors will pave the way for a new class of tools for the study of microRNAs. This will be a major new direction that will spark a range of equivalent studies in other cell lines and with other microRNAs. Broader impact: The experiments will be performed in NCI-60 colon, hematologic, lung, and pancreatic tumor cell lines. The criteria for the selection of the particular cell lines was based: on the prevalence of lung cancer and colon cancer in the United States (the leading cause of cancer death for both men and women and the second leading cause of cancer deaths for both men and women combined, respectively); because pancreatic and hematologic cancers have very poor 5-year survival (pancreatic cancer in particular) underscoring the urgent need for new diagnostic and treatment tools. The collection of monoclonal cell lines harboring the biomolecular networks will be made available to the scientific community. The proposed research will also form an educational platform where students will be exposed to an integrated research environment, combining theory and experiments at the intersection of biology and engineering.

癌症是一类细胞疾病，其特征是不受控制的生长，侵袭和转移。尽管癌症是由复杂的潜在遗传决定因素进行多方面的，但新兴的证据表明，在不同组织和癌症类型的细胞内信号传导水平上，常见的特征。能够检测细胞内分子信号组合的系统在单细胞水平上对疾病的诊断，预防，治疗和监测具有显着潜力。最近，科学家开发了第一代遗传回路和传感器，这些电路和传感器作为细胞中的信息处理系统运行。拟议的研究将开发和研究旨在检测和监测内源性microRNA的分子生物传感器，内源性microRNA是一类无编码的RNA，通过靶向RNA转录物来调节基因表达。拟议的研究的目标是：（a）设计和优化对内源性microRNAS组合的敏感性和特异性响应的分子生物传感器，（（b）基于NCI-60小组的综合生物传感器，开发单克隆肿瘤细胞系，并通过NCI-60小组和（c）通过对疾病进行疾病的关系来响应疾病的关系，以响应其对疾病的关系。在包括癌症在内的发育和疾病中成为重要的调节剂。实验证据暗示了大多数人类恶性肿瘤中异常的microRNA表达谱。可靠地处理microRNA信息的能力（具有单细胞分辨率）将生成用于基本癌症研究的新工具，并导致新的癌症治疗方式。具体而言，microRNA生物传感器在肿瘤细胞系中的应用将显着提高我们对生物细胞中microRNA表达和动力学的理解。使用选定的MicroRNA传感器的单克隆细胞系的开发将为研究microRNA的新工具铺平道路。这将是一个主要的新方向，它将在其他细胞系和其他microRNA中引发一系列等效研究。更广泛的影响：实验将在NCI-60结肠，血液学，肺和胰腺肿瘤细胞系中进行。选择特定细胞系的标准是基于：美国的肺癌和结肠癌的患病率（男性和女性癌症死亡的主要原因，以及男性和女性癌症死亡的第二大主要原因，分别是合并的）；由于胰腺和血液学癌症的5年生存率非常差（尤其是胰腺癌）强调了对新诊断和治疗工具的迫切需求。具有生物分子网络的单克隆细胞系的收集将提供给科学界。拟议的研究还将组成一个教育平台，将学生接触到一个综合的研究环境，并将理论和实验结合在生物学与工程的交集中。