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，它们是彼此的镜像，但在其他方面无法区分，比如左手和右手。自然界中的所有DNA分子都含有右旋糖类，这会使它们呈现出众所周知的双螺旋形状，并带有右旋扭曲。自然界中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。然而，当这些装置被引入细胞中时，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，左手DNA在自然界中不存在，并且能抵抗这种形式的降解。特别是，该项目将开发(1)输入接口，用于从感兴趣的目标，如小分子或天然脱氧核糖核酸(D-DNA)向左旋脱氧核糖核酸(L-脱氧核糖核酸)发出信号，以及(2)输出接口，用于从左旋脱氧核糖核酸返回相关的自然分子途径(如脱氧核糖核酸的翻译和转录)。这一发展将使未来的设备能够感知细胞状态(健康或疾病)的多个标记，然后使用DNA计算整合传感器，并最终作用于细胞，例如在疾病时摧毁细胞，但设备本身将主要由左手DNA组成，因此在细胞中将是健壮的。该项目将涉及研究生和本科生。它将是跨学科的，涉及计算机科学和生物医学工程，将在新墨西哥大学和哥伦比亚大学进行。该项目的第一个目标是研究L-左手DNA分子逻辑器件与自然发生的分子之间的结合作用。这项研究将产生一个基本技术工具箱，用于实现输入接口，这些输入接口可以检测自然产生的目标分子，进而可以翻译这些结合事件，用于生物正交L-DNA逻辑电路中的信息处理。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系统能够通过编程的分子计算对环境产生某种影响(即执行某种形式的驱动)。具体地说，该项目将专注于从L-脱氧核糖核酸分子逻辑电路中产生有用输出信号的一种特殊机制，即通过L-脱氧核糖核酸分子电路对隔离的反义D-核酸进行变构“激活”而击倒基因。总而言之，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启动的机制。这一奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。