Collaborative Research: Functionalized Nano-Textured Surfaces to Isolate and Identify Bladder Cancer Cells

合作研究：功能化纳米纹理表面分离和鉴定膀胱癌细胞

• 批准号: 1407219
• 负责人: Yair Lotan
• 金额: $ 15.01万
• 依托单位: University of Texas Southwestern Medical Center
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1407219&HistoricalAwards=false
• 关键词: Collaborative; Research; Functionalized; Nano; Textured

The high mortality rate of patients with invasive and metastatic cancer has changed little over the past few decades. Early detection is crucial for better treatment of cancer and to increase survival rates. Traditional diagnostic approaches fail to detect some types of cancers at very early stages. Bladder cancer is usually silent in early stages resulting in diagnosis at late and often incurable stages. Occasionally, the symptoms of both benign conditions and bladder cancer are nonspecific and very similar. In about 85% of cancer patients, there may be red blood cells present in the urine. But the same symptoms may be the result of an infection or inflammation in the urinary tract (kidney, bladder, prostate). This proposal aims at providing a non-invasive, low-cost, highly sensitivity, and ultra-specific approach using solid-state microdevices and biochemical functionalization of chip surfaces. The functionalization will target the molecules that are overexpressed on tumor cells. Automation of the data acquisition and analysis will be done to determine physical behavioral differences and biomarker expression levels between tumor and normal cells. The molecules chosen for targeted detection of tumor cells will add significant value as indicators and predictors of the outcomes of the treatment. This proposal will change how cancers, and especially bladder cancer, are diagnosed. The experiments will be done first with cultured cells, then with cells isolated from the blood of animals bearing human bladder cancer xenografts, and finally with real patient clinical samples. The multi-disciplinary team will integrate the novel technology that will provide educational opportunities for students on the whole continuum of K-Grad. Graduate and undergraduate students will be engaged and introduced to exciting new dimensions of cell biology, biochemistry and solid-state fabrication through development of a cross-listed course module on the cell-nano interface. The research outcomes will be also used to develop participatory modules at College of Engineering summer camps to attract future adults to STEM careers. The results, data and outcomes of the research and education endeavors will be disseminated not only through peer-reviewed articles and conferences, but also through social and public media. The novelty of the proposal lies in three elements: first, a special class of probe molecules called aptamers will be used. Aptamers can be reversibly denatured, and these will therefore provide a mechanism for the reversible release of tumor cells in their native states. Second, the nanotextured substrates will provide biomimetic environment to examine the cell behavior. Third, dynamic behavior of tumor cells will be used to measure the temporal evolution of cell-cell interactions over days at single-cell or sub-cellular scales. This new tumor detector will serve as a non-invasive cell type reporter (without "staining" the cell), and as a cell culture substrate with prescribed behavior of cells for certain level of biomarker overexpression. Currently such a platform does not exist. The technological integration described in this proposal may therefore provide early means of identifying remission or metastases, and even give some insights into how many and what types of metastases may be present in a given sample.

在过去的几十年中，侵入性和转移性癌症患者的高死亡率较高。早期检测对于更好地治疗癌症和提高存活率至关重要。传统的诊断方法无法在很早的阶段检测到某些类型的癌症。膀胱癌通常在早期阶段保持沉默，从而在较晚且通常无法治愈的阶段进行诊断。有时，良性疾病和膀胱癌的症状都是非特异性的，而且非常相似。在约85％的癌症患者中，尿液中可能存在红细胞。但是同样的症状可能是尿路感染或炎症的结果（肾脏，膀胱，前列腺）。该提案旨在使用固态微电视和芯片表面的生化功能化提供非侵入性，低成本，高度敏感性和超特异性方法。功能化将靶向在肿瘤细胞上过表达的分子。将进行数据获取和分析的自动化，以确定肿瘤和正常细胞之间的身体行为差异和生物标志物表达水平。选择用于靶向检测肿瘤细胞的分子将为治疗结果的指标和预测指标增加重要的价值。该建议将改变癌症，尤其是膀胱癌的诊断方式。实验将首先使用培养的细胞进行，然后将细胞从带有人膀胱癌异种移植的动物的血液中分离出来，最后是实际患者的临床样品。多学科团队将整合新的技术，该技术将为整个K-Grad的学生提供教育机会。通过开发细胞 - 纳米界面上的跨上市课程模块，研究生和本科生将参与并引入细胞生物学，生物化学和固态制造的新维度。该研究成果还将用于在工程夏令营开发参与模块，以吸引未来的成年人从事STEM职业。研究和教育努力的结果，数据和成果将不仅通过同行评审的文章和会议来传播，还通过社会和公共媒体传播。该提案的新颖性在于三个要素：首先，将使用一种特殊的探针分子，称为Aptamers。适体可以是可逆性变性的，因此，这些适体将提供一种机制，可以使其本地肿瘤细胞可逆释放。其次，纳米刺激的底物将提供仿生环境来检查细胞行为。第三，肿瘤细胞的动态行为将用于测量单细胞或亚细胞尺度上几天内细胞 - 细胞相互作用的时间演化。该新的肿瘤检测器将用作非侵入性细胞类型报告基因（无需“染色”细胞），并且是针对某些生物标志物过表达水平的细胞规定行为的细胞培养底物。当前，这种平台不存在。因此，本提案中描述的技术整合可以提供鉴定缓解或转移的早期手段，甚至可以深入了解给定样本中可能存在多少种和哪种类型的转移。