Nanopatch System for Next Generation Ion Channel Recordings

描述（由申请人提供）：离子通道是一系列生物功能的控制机制。医学研究人员每年发现数十或数百种新的渠道病，因为许多疾病被认为是由渠道功能障碍引起的。此外，某些药物对离子通道的不良副作用有可能在体内引起致命反应。因此，离子通道的整个生物学、分子生物学和生物物理学具有重要的医学意义。通道也是固有的多尺度装置，它将原子尺度结构与宏观流动联系起来，响应具有大量电流的单个分子。目前用于研究这种电流流动的膜片钳方法在两个关键区域受到限制，以最大限度地从研究这些通道中获得信息。首先，当前的系统无法达到足够低的噪声水平，以测量许多具有低电导的通道，例如Ca通道。其次，这些系统无法达到足够大的带宽来检测在许多通道（如Na通道）中看到的许多短持续时间的单通道事件。这个提议的项目旨在进一步发展一个玻璃纳米孔系统，这个系统以前是在DARPA的一个项目下开发的，它可以成为一个纳米贴片装置，能够测量单通道电流。该装置由一种新的膜结构组成，该结构由一个纳米级孔（10 nm至75 nm半径）组成，该孔位于被脂质双分子层覆盖的毫米级玻璃表面。新的纳米贴片技术提供了提高低频测量灵敏度和提高高工作频率的可能性，这将代表科学测量能力的真正进步。第一阶段SBIR计划的总体目标是建立具体的实施例或实施例的组合，因此新的脂质在玻璃纳米孔上的配置可以最好地应用于改进实验室中最先进的离子通道测量。这项研究将由犹他大学的亨利·怀特博士进行，他的实验室帮助开发了玻璃纳米孔。本课题提出了一种提高离子通道电流测量技术质量的新系统。这种技术上的改进可能会导致更好的药物开发和筛选方法，并提供测试实验药物对离子通道的影响的能力，从而对体内许多过程产生影响，而不必实际给志愿者服用药物。此外，所提出的技术可以精确测量特定离子通道电流，并可能开发针对这些通道活动的新药。最后，提出的技术改进将为生物分子研究界带来可观的利益。

DESCRIPTION (provided by applicant): Ion channels are the control mechanisms of an enormous range of biological functions. Medical researchers are discovering tens or hundreds of new channelopathies per year as many diseases are being recognized that arise from channel malfunction. In addition, the adverse side effects of some drugs on ion channels have the potential to cause lethal reactions within the body. The entire biology, molecular biology, and biophysics of ion channels is thus of great medical importance. Channels are also inherently multiscale devices that link atomic scale structures to macroscopic flows responding to single molecules with substantial current flow. Current patch clamp methods used to study this current flow are limited in two key areas to maximize the information that can be gained from studying these channels. First, current systems cannot achieve a low enough noise level to measure many channels with low conductances, such as the Ca channels. Secondly, these systems are unable to reach a large enough bandwidth to detect many short duration single channel events seen in many channels such as the Na channel. The proposed project aims to further develop a glass nanopore system, previously developed under a DARPA project, into a nanopatch device capable of measuring single channel currents. This device consists of a new membrane configuration comprised of a nanometer-scale pore (10 nm to 75 nm radius) in a millimeter-scale glass surface covered by a lipid bilayer. The new nanopatch technology offers the possibility of increasing measurement sensitivity at low frequencies, and increasing the upper operating frequency, which would represent a real advance in scientific measurement capability. The overall aim of this Phase I SBIR program is to establish the specific embodiment, or combination of embodiments, for which the new lipid on glass nanopore configuration can best be applied to improve on the state-of-the-art in laboratory ion channel measurements. This investigation will be conducted with Dr. Henry White from the University of Utah, whose lab helped develop the glass nanopores. This project proposes a new system to improve the quality of ion channel current measurement technology. Such an improvement in the technology could lead to better methods for drug development and screening and offer the capability to test experimental drugs' effect on ion channels, and thus on many processes in the body, without actually having to give the drug to volunteers. In addition, the proposed technology could make possible accurate measurements of specific ion channel currents and might enable development of new drugs to target the activities in those channels. Finally, the technological improvements proposed would bring considerable benefit to the biomolecular research community.