Biotechnology Resource Center of BioModular Multi-scale Systems (CBM2) for Precision Medicine

精准医学生物模块多尺度系统生物技术资源中心(CBM2) 总体而言：开发实现精确医学的新技术 摘要/摘要 液体活组织检查是对体外诊断(IVDS)的一项令人兴奋的贡献，因为它具有微创 保护标记的性质、过多的标记类型(循环生物细胞、无细胞分子[蛋白质、 微型RNA、无细胞DNA]和胞外小泡[外切体])，以及它们的各种分子信息 拿着。不幸的是，这些标记物中的许多没有在临床上得到充分利用，主要是因为疾病- 相关的液体活检标记物在混合人群中可能占绝大多数，这使得他们很难找到和 分析。这在一定程度上是因为缺乏有效隔离的平台和分析有限的 液体活组织检查分离物中包含的患病分子的数量。例如，单个循环中的肿瘤细胞 (CTC)携带者~6pg基因组DNA。下一步生成测序(NGS)需要大约30 ng的输入核酸 材料。因此，必须使用高水平的扩增来分析单个CTC，这可能会造成偏见 代表基因组和/或掩盖重要的分子特征，如表观遗传修饰。 精密医学生物模块化多尺度系统(CBM2)生物技术资源中心 寻求通过提供处理液体活组织检查的新的创新平台技术来发展其愿景 记号笔。平台技术将拥有分离与疾病相关的液体活组织检查标记的能力 (来自活性P41中心的输出)，并使用无扩增分析来分析它们的分子货物 具有足够的灵敏度来处理单分子(这是新的应用)。这将通过三个方面来实现 聚焦紧密，但互动性很强的翻译研究和开发努力：(1)固相酶 用于单分子检测和鉴定的纳米级反应器和纳米电泳法；(2)无标记 使用双纳米孔飞行时间(TOF)传感器的检测策略稳定在流体网络中以读取 用于高效鉴定的单分子飞行时间；以及(3)混合尺度(nm→mm)和模块化流体 由使用稳健策略组装的特定任务模块组成的系统。该模块化系统可以 在扩增中对从液体活组织检查标记获得的分子实体进行单分子处理- 具有全流程自动化的自由格式。将CBM2的S平台技术交付给生物医学界 将通过该中心运营的芯片生产流水线实现。 CBM2由一支非常有成就的多学科团队组成，他们精通于成功的生产 大型多机构项目的成果。该中心的研究将得到广泛的 中心目前的运作阶段(2015-2020年)的基础设施是否到位。智能交通运输系统的翻译 平台技术进入生物医学界将通过参与性的培训/传播得到促进 计划，以及积极的协作和服务项目组合。在中心的新平台上进行培训 将通过研讨会和CBM2成员广泛的研究和临床网络促进技术的发展。 新发现的传播将通过一个强大的网站、访问学者、会议 参与、及时出版以及商业实体的参与。

TITLE: Biotechnology Resource Center of BioModular Multi-scale Systems (CBM2) for Precision Medicine Overall: Developing New Technologies for Enabling Precision Medicine Abstract/Summary Liquid biopsies represent an exciting contribution to in vitro diagnostics (IVDs) because of the minimally invasive nature of securing markers, the plethora of marker types (circulating biological cells, cell-free molecules [proteins, micro-RNA, cell-free DNA], and extracellular vesicles [exosomes]), and the diverse molecular information they carry. Unfortunately, many of these markers have not been fully utilized in the clinic primarily because disease- associated liquid biopsy markers can be a vast minority in a mixed population making them difficult to find and analyze. This is partly due to a lack of platforms for their efficient isolation and tools to analyze the limited numbers of diseased molecules contained in a liquid biopsy isolate. For example, a single circulating tumor cell (CTC) carriers ~6 pg of genomic DNA. Next Generate Sequencing (NGS) requires ~30 ng of input nucleic acid material. Thus, high levels of amplification must be used to analyze a single CTC, which can create biased representation of the genome and/or mask important molecular features, such as epigenetic modifications. The Biotechnology Resource Center of BioModular Multi-scale Systems (CBM2) for Precision Medicine is seeking to evolve its vision with the delivery of new and innovative platform technologies to process liquid biopsy markers. The platform technologies will possess the ability to isolate disease-associated liquid biopsy markers (outputs from the active P41 Center) and analyze their molecular cargo using amplification-free assays with sufficient sensitivity to process single molecules (new to this application). This will be realized through three tightly focused, yet highly interactive Translational Research and Development efforts: (1) Solid-phase enzymatic nanoscale reactors and nano-electrophoresis for detection and identification of single-molecules; (2) label-free detection strategies using dual-nanopore time-of-flight (TOF) sensor poised within a fluidic network to read the TOF of single molecules for highly efficient identification; and (3) mixed-scale (nm → mm) and modular fluidic systems comprised of task-specific modules assembled using robust strategies. The modular system can perform single-molecule processing of a molecular entity secured from a liquid biopsy marker in an amplification- free format with full process automation. Delivery of CBM2's platform technologies to the biomedical community will be realized through a production pipeline of chips operated by the Center. CBM2 consists of a highly accomplished and multidisciplinary team that is well versed in producing successful outcomes from large multi-institutional projects. The Center research will be facilitated by the extensive infrastructure in place as a result of the Center's current phase of operation (2015 – 2020). Translation of its platform technologies into the biomedical community will be facilitated by an engaging training/dissemination program, and an aggressive Collaborative and Service Project portfolio. Training on the Center's new platform technologies will be facilitated through workshops and CBM2 members' extensive research and clinical networks. Dissemination of new discoveries will be facilitated through a robust website, visiting scholars, meeting participation, and timely publications as well as the involvement of commercial entities.