SHF: Collaborative Research: Biocompatible I/O Interfaces for Robust Bioorthogonal Molecular Computing

SHF：协作研究：用于稳健生物正交分子计算的生物相容性 I/O 接口

• 批准号: 1763632
• 负责人: Milan Stojanovic
• 金额: $ 10万
• 依托单位: Columbia University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-10-01 至 2022-09-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1763632&HistoricalAwards=false
• 关键词: SHF; Collaborative; Research; Biocompatible; Interfaces

Sugar molecules can exist in two forms that are the mirror image of each other but otherwise indistinguishable, like the left and right hand. All DNA molecules in nature contain right-hand sugars that cause them to assume the well-known double-helix shape with a right-handed twist. Proteins in cells in nature recognize the right-handed DNA in order to perform useful cellular functions, one of which is destroying single-stranded DNA. Over the last decade, DNA has come to be used in synthetic devices for sensing, computing, and diagnosing pathogens and disease. However, when these devices are introduced into a cell, they are prone to being destroyed by these proteins. This project will develop devices using left-handed DNA, which is not found in nature and is resistant to this form of degradation. In particular, the project will develop (1) input interfaces, for signaling from targets of interest, such as small molecules or natural DNA (D-DNA), to left-handed DNA (L-DNA), and (2) output interfaces, for signaling from left-handed DNA back into a relevant natural molecular pathway (such as DNA translation and transcription). This development will enable future devices that can sense multiple markers of the state of a cell (healthy or diseased), then integrate the sensors using DNA computing, and finally act on the cell, for example to destroy it if diseased, but the device itself will consist mainly of left-handed DNA and will therefore be robust in the cell. The project will involve both graduate and undergraduate students. It will be interdisciplinary, involving computer science and biomedical engineering, and will be carried out at the University of New Mexico and Columbia University.The first aim of the project is to study the binding interactions between L-DNA (left-handed DNA) molecular logic devices and naturally occurring molecules. This study will produce a toolbox of basic techniques for implementing input interfaces that can detect naturally occurring target molecules, which in turn, can translate those binding events for information processing within a bio-orthogonal L-DNA logic circuit. This will be done by characterizing the actuation of hybrid L-DNA/D-DNA molecular computing components by pure D-DNA input strands. The second aim of the project is developing output interfaces that will enable L-DNA systems to produce some effect on the environment (i.e., carry out some form of actuation) as a result of their programmed molecular computations. Specifically, the project will focus on one particular mechanism for generating a useful output signal from an L-DNA molecular logic circuit, namely, gene knockdown by the allosteric "activation" of sequestered antisense D-nucleic acids by an L-DNA molecular circuit. Together, these will provide a mechanism for L-DNA molecular logic circuits to actuate via control of gene expression.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

糖分子可以以两种形式存在，它们互为镜像，但在其他方面无法区分，就像左手和右手一样。自然界中的所有 DNA 分子都含有右手糖，使它们呈现出众所周知的右旋双螺旋形状。自然界细胞中的蛋白质识别右手DNA以执行有用的细胞功能，其中之一是破坏单链DNA。在过去的十年中，DNA 已被用于传感、计算和诊断病原体和疾病的合成设备中。然而，当这些装置被引入细胞时，它们很容易被这些蛋白质破坏。该项目将开发使用左手DNA的设备，这种DNA在自然界中不存在，并且能够抵抗这种形式的降解。特别是，该项目将开发 (1) 输入接口，用于从小分子或天然 DNA (D-DNA) 等感兴趣的目标向左手 DNA (L-DNA) 发出信号，以及 (2) 输出接口，用于从左手 DNA 发出信号返回相关的自然分子途径（例如 DNA 翻译和转录）。这一发展将使未来的设备能够感知细胞状态的多个标记（健康或患病），然后使用 DNA 计算集成传感器，最后对细胞起作用，例如在患病时摧毁它，但设备本身主要由左手 DNA 组成，因此在细胞中很稳定。该项目将涉及研究生和本科生。该项目将是跨学科的，涉及计算机科学和生物医学工程，并将在新墨西哥大学和哥伦比亚大学进行。该项目的首要目标是研究L-DNA（左手DNA）分子之间的结合相互作用。逻辑器件和自然发生的分子。这项研究将产生一个用于实现输入接口的基本技术工具箱，该输入接口可以检测自然发生的目标分子，进而可以将这些结合事件转化为生物正交L-DNA逻辑电路内的信息处理。这将通过表征纯 D-DNA 输入链对混合 L-DNA/D-DNA 分子计算组件的驱动来完成。该项目的第二个目标是开发输出接口，使 L-DNA 系统能够通过其编程的分子计算对环境产生一些影响（即执行某种形式的驱动）。具体来说，该项目将重点关注一种从 L-DNA 分子逻辑电路产生有用输出信号的特定机制，即通过 L-DNA 分子电路对隔离的反义 D-核酸进行变构“激活”来实现基因敲除。这些将为 L-DNA 分子逻辑电路提供一种通过控制基因表达来驱动的机制。该奖项反映了 NSF 的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。