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

标题：精准医学生物模块化多尺度系统（CBM 2）生物技术资源中心 总体：开发新技术以实现精准医疗 摘要/概要 液体活检代表了体外诊断（IVD）的一个令人兴奋的贡献，因为微创 固定标记物的性质、过多的标记物类型（循环生物细胞，无细胞分子[蛋白质， micro-RNA，无细胞DNA]和细胞外囊泡[外来体]），以及它们所包含的各种分子信息。 携带.不幸的是，这些标记物中的许多尚未在临床上充分利用，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是极少数， 分析。这部分是由于缺乏有效隔离的平台和分析有限的 液体活检分离物中包含的患病分子的数量。例如，单个循环肿瘤细胞 (CTC)载体~6 pg基因组DNA。下一代测序（NGS）需要约30 ng输入核酸 材料因此，必须使用高水平的扩增来分析单个CTC，这可能产生偏差。 这可能是基因组的代表性和/或掩盖重要的分子特征，如表观遗传修饰。 精准医学生物模块化多尺度系统（CBM 2）生物技术资源中心是 通过提供新的创新平台技术来处理液体活检， 标记。该平台技术将具备分离疾病相关液体活检标记物的能力 （来自活跃的P41中心的输出），并使用无扩增测定分析其分子货物， 处理单个分子的足够灵敏度（对于本申请是新的）。这将通过三个 密切关注，但高度互动的转化研究和开发工作：（1）固相酶 纳米反应器和纳米电泳用于检测和识别单分子;（2）无标记 使用在流体网络内保持平衡的双纳米孔飞行时间（TOF）传感器来读取纳米颗粒的检测策略。 用于高效识别的单个分子的TOF;以及（3）混合尺度（nm → mm）和模块化流体 系统由使用强大策略组装的特定任务模块组成。模块化系统能够 - 在扩增中对从液体活检标记物固定的分子实体进行单分子处理， 自由格式，全过程自动化。向生物医学界提供CBM 2的平台技术 将通过该中心运营的芯片生产管道实现。 CBM 2由一个高度成就和多学科的团队组成，他们精通生产成功的 大型多机构项目的成果。该中心的研究将得到广泛的促进， （c）由于中心目前的运作阶段（2015 - 2020年），基础设施已经到位。其翻译 将通过参与培训/传播促进平台技术进入生物医学界 计划，以及积极的协作和服务项目组合。中心新平台上的培训 将通过研讨会和CBM 2成员广泛的研究和临床网络促进技术的发展。 将通过一个强大的网站、访问学者、 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.