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. ? ? ?
