Nanopatch System for Next Generation Ion Channel Recordings

描述(由申请人提供)：离子通道是广泛的生物功能的控制机制。随着人们认识到许多疾病是由通道故障引起的，医学研究人员每年发现数十或数百种新的通道病。此外，一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都具有重要的医学意义。通道本质上也是多尺度装置，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。目前用于研究这一电流的膜片钳方法仅限于两个关键区域，以最大限度地获得从研究这些通道中获得的信息。首先，目前的系统不能达到足够低的噪声水平来测量许多低电导的通道，如钙通道。其次，这些系统无法达到足够大的带宽来检测在许多通道中看到的许多短持续时间的单通道事件，例如Na通道。拟议的项目旨在将之前在DARPA项目下开发的玻璃纳米孔系统进一步开发成能够测量单通道电流的纳米晶片设备。这种装置由一种新的膜结构组成，该膜由毫米尺度的玻璃表面上的纳米孔(半径为10 nm到75 nm)组成，表面覆盖着一层脂质双层。新的纳米晶片技术提供了在低频下提高测量灵敏度和提高上限工作频率的可能性，这将代表着科学测量能力的真正进步。该第一阶段SBIR计划的总体目标是建立特定的实施例或实施例的组合，对于该具体实施例或实施例的组合，可以最好地应用新的玻璃纳米孔上的脂类配置，以改进实验室离子通道测量的最先进水平。这项研究将与犹他大学的亨利·怀特博士一起进行，他的实验室帮助开发了玻璃纳米孔。本课题提出了一种新的系统来提高离子通道电流测量技术的质量。这种技术上的改进可能会带来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，从而测试体内许多过程的能力，而无需将药物实际给予志愿者。此外，拟议的技术可以准确测量特定的离子通道电流，并可能开发针对这些通道中的活动的新药。最后，建议的技术改进将给生物分子研究界带来相当大的好处。

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.