Small Molecule Inhibitors of ZAP-70 for the Treatment of Autoimmune Disorders

DESCRIPTION (provided by applicant): Patch clamp electrophysiology has been a central tool of neuroscience and pharmaceutical research since its advent in the late 1970s. Whole-cell patch clamping utilizes glass micropipettes and sensitive analog electronics to monitor the ion-channel currents and intracellular voltages of individual neurons or other cells. For decades, this has been performed by highly trained scientists using micromanipulators under a microscope to painstakingly guide an electrode to contact (or patch clamp ) a single cell. Once in contact, large, expensive amplifier modules are used to monitor or manipulate the small cellular electrical signals. In the last ten years, advances in automation have led to the development of inexpensive robotic systems capable of automatically patch clamping many neurons in vivo in minutes, with success rates matching or exceeding those of skilled investigators. As a result of this innovation, patch clamp techniques are being adapted to a wider variety of experimental protocols and target species, and researchers are now recording from multiple cells simultaneously. However, the size and expense of the traditional rack-mounted amplifier electronics systems present a significant bottleneck in the continued development of large-scale highly automated intracellular recording systems. Single-channel amplifiers capable of current-clamp and voltage- clamp measurements are typically large rack-mounted boxes weighing several kilograms and costing nearly 10,000 per channel. At least eight companies produce such instruments, which represent the dominant component of modern patch clamp recording systems in terms of size, mass, and cost. The move to multi- channel automated systems will only exacerbate this problem. IntanTechnologies proposes to integrate all the sensitive electronics needed for patch clamp recording onto a small, low-power, inexpensive silicon microchip ( PatchChip ) that will replace traditional patch clamp amplifiers. The use of advanced microelectronics will reduce the bulky and expensive amplifier systems down to the size of a postage stamp. Integrated amplifiers could be mounted in close proximity to each micropipette in a large-scale automated recording system, reducing noise pickup and size. The PatchChip will have the capability to conduct both voltage-clamp and current-clamp measurements, and will have sufficient sensitivity to resolve picoampere-level synaptic currents and millivolt-level intracellular voltages. A novel circuit architecture eliminates the need for off-chip precision resistors and allows for standard patch clamp functions like series resistance compensation and fast transient capacitance compensation. An easy-to-use USB interface circuit board will be designed for the chip; this evaluation system with open-source software will allow instrumentation manufacturers to incorporate this new technology into advanced patch clamp systems. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: The proposed program seeks to develop a microchip ( PatchChip ) to reduce the size and cost of monitoring electrical activity in nerve cells. Integrating sensitive amplifier electronics onto a single silicon chip will facilitate the developmnt of large-scale neural recording systems for scientificand medical research.