Feedback Control of Biological Polymers in a Nanopore

纳米孔中生物聚合物的反馈控制

• 批准号: 7687632
• 负责人: William Bruce Dunbar
• 金额: $ 16.6万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA CRUZ
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7687632
• 关键词: Affect; Algorithms; Base Sequence; Bioinformatics; Biological; Biology; Cell Count; Cell Differentiation process; Cells; Computer software; Cytosine; DNA Sequence; Data; Detection; Development; Devices; Disease; Electronics; Embryology; Event; Feedback; Frequencies; Genome; Genomics; Goals; Health; Hemolysin; Human; Lead; Learning; Machine Learning; Measurement; Measures; Membrane; Messenger RNA; Methods; Molecular; Molecular and Cellular Biology; Nucleotides; Other Genetics; Patients; Pharmacogenomics; Physics; Poly C; Poly U; Polymers; RNA; Reading; Recording of previous events; Research; Research Personnel; Resolution; Sampling; Scanning; Signal Transduction; Speed; Technology; Time; Training; Translating; Uracil; Variant; Vision; base; cell analyzer; copolymer; design; improved; laptop; mammalian genome; nanopore; novel; programs; response; single molecule; success; technology development; tool; voltage

DESCRIPTION (provided by applicant): Electronic sequencing in nanopores shows great promise for inexpensive DNA sequencing at high speed and with minimal preparative steps. Such capability would lead to efficient reading of human SNPs or other genetic variations, which would in turn have a significant impact in pharmacogenomics and other disease treatments and preventions based on information from the patient's own genome. Recently, researchers identified the inability to regulate the speed of a molecule's translocation through the pore as the primary obstacle to realizing the sequencing potential of hemolysin nanopores. The proposed research will investigate the application of feedback control to substantially improve the ability to regulate molecule translocation speeds in a nanopore, thereby improving the ability to sequence with existing nanopore technology. In particular, the primary goal is to design novel hardware and software algorithms for feedback control of single polymers in a hemolysin nanopore on a microsecond time scale and with near angstrom precision. Such capability would contribute to the development of nanopore-based sequencing technologies, augment the efforts of the $1000/mammalian genome project, and be a revolutionary contribution to the realm of applied feedback control. The control algorithms would also leverage the long-term objective of the proposed effort: the development of a nanopore-based single cell analyzer. The device would enable one to efficiently determine the concentration of all mRNA in a single cell at an instant of time. This technology would improve the ability to accurately track molecular events that occur during cell differentiation, by reducing the number of cells required for event detection and increasing the time resolution of detection measurements. There are two primary aspects to the proposed research program that are necessary augmentations to my expertise in control. First, I will engage in a two-year intensive period of didactic training in relevant courses, including molecular and cellular biology, embryology, cell signaling, genomics and bioinformatics. The basic understanding gained is required for success in the application of control to problems in human health broadly, and in technology development for cell interrogation specifically. Second, I will participate in the $1000/mammalian genome project to learn about the physics and biology of the hemolysin nanopore. In parallel to the $1000 genome project, I will explore the controlled capabilities of the nanopore for efficient mRNA sequencing, using tools from bioinformatics and machine learning to translate the controlled response data into the identity of unknown nucleotides.

描述（由申请人提供）：纳米孔中的电子测序显示出以最少的制备步骤进行高速且廉价的 DNA 测序的巨大前景。这种能力将有助于有效读取人类 SNP 或其他遗传变异，进而对基于患者自身基因组信息的药物基因组学和其他疾病治疗和预防产生重大影响。最近，研究人员发现无法调节分子通过孔的易位速度是实现溶血素纳米孔测序潜力的主要障碍。 拟议的研究将研究反馈控制的应用，以大幅提高调节纳米孔中分子易位速度的能力，从而提高现有纳米孔技术的测序能力。特别是，主要目标是设计新颖的硬件和软件算法，以微秒时间尺度和接近埃的精度对溶血素纳米孔中的单一聚合物进行反馈控制。这种能力将有助于基于纳米孔的测序技术的发展，增强每个哺乳动物基因组项目 1000 美元的努力，并对应用反馈控制领域做出革命性的贡献。控制算法还将利用所提议工作的长期目标：开发基于纳米孔的单细胞分析仪。该装置将使人们能够在某一时刻有效地测定单个细胞中所有 mRNA 的浓度。该技术将通过减少事件检测所需的细胞数量并提高检测测量的时间分辨率，提高准确跟踪细胞分化过程中发生的分子事件的能力。 拟议的研究计划有两个主要方面是对我在控制方面的专业知识的必要补充。首先，我将进行为期两年的相关课程强化教学培训，包括分子和细胞生物学、胚胎学、细胞信号传导、基因组学和生物信息学。要成功地将控制应用于广泛的人类健康问题，特别是细胞询问的技术开发，需要获得基本的理解。其次，我将参加1000美元/哺乳动物基因组项目，了解溶血素纳米孔的物理和生物学。与 1000 美元的基因组项目并行，我将探索纳米孔的受控能力，以实现有效的 mRNA 测序，使用生物信息学和机器学习的工具将受控响应数据转化为未知核苷酸的身份。