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Development of a disposable cell-free ion channel measurement platform for hERG s

开发用于 hERG 的一次性无细胞离子通道测量平台

基本信息

批准号：
8213427
负责人：
Jason L. Poulos
金额：
$ 35.7万
依托单位：
LIBREDE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2013-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8213427
关键词：
Area Arrhythmia Artificial Membranes Biological Assay Businesses California Cardiac Cardiac Death Cell Line Cell membrane Cells Collaborations Collection Development Drug Delivery Systems Drug Formulations Drug Interactions Equipment Foundations Freedom Freezing Goals Housing Human Human Resources Ion Channel Lead Legal patent Libraries Los Angeles Measurement Measures Membrane Methods Pharmacologic Substance Phase Physiological Processes Play Preclinical Drug Evaluation Preparation Process Production Proteins Protocols documentation Research Research Personnel Risk Safety Sampling Screening procedure Shipping Ships Solutions System Technology Testing Training Transmembrane Transport Universities Validation Water Work assay development channel blockers cost drug candidate high throughput screening instrumentation novel patch clamp professor prototype public health relevance reconstitution relating to nervous system single molecule

项目摘要

DESCRIPTION (provided by applicant): Assaying ion channels for pharmaceutical discovery and safety screening is problematic to perform in high throughput because the ion channels must be incorporated into a cell membrane to allow measurement of their ionic transport to determine their functionality. As a result, there are currently no high quality, high throughput assays for ion channel screening. Recent developments of automated patch clamp instrumentation are still over an order of magnitude lower throughput than conventional drug screening for soluble proteins and also require expensive instrumentation, specialized cell lines, and consumables. For existing methods of ion channel screening, there is a large gap in information quality, throughput, and cost. Librede Inc. is developing an alternative cell-free technology for ion channel screening using artificial cell membranes. Librede's patent pending formulation of cell-free artificial membranes can enable higher throughput and lower consumable costs while requiring less expensive equipment and trained personnel. Librede was founded by UCLA researchers and the inventors of this technology. In the work proposed here, we aim to develop materials and methods for measurement and packaging of the hERG channel in our artificial membrane platform. hERG is an important ion channel to screen, since off-target activity of pharmaceuticals on the hERG channel can lead to cardiac arrhythmia and death; thus all drug candidates, irrespective of target, must be screened against interaction with hERG. For this work, we will collaborate with the Schmidt group at UCLA, who has demonstrated the measurement of hERG in artificial membranes in preliminary work, a first. We aim to determine the compatibility of hERG with Librede's artificial membrane platform and determine the conditions with optimize the long term storage of hERG packaged with our membrane array plates. Finally, we will perform a demonstration of our technology by screening hERG against known channel blockers over a 48 membrane array plate simultaneously. This work is a key step toward our goal of reducing the cost and expertise required for ion channel screening. PUBLIC HEALTH RELEVANCE: We have recently developed a novel ion channel measurement platform that may be indefinitely stored, commercially shipped, and requires very little input from the end user to operate. We aim to validate this platform with the human cardiac ion channel hERG to demonstrate the utility of this technology for ion channel screening.

描述（由申请人提供）：测定用于药物发现和安全性筛选的离子通道对于以高通量进行是有问题的，因为离子通道必须被并入细胞膜中以允许测量它们的离子转运以确定它们的功能。因此，目前没有用于离子通道筛选的高质量、高通量测定。自动化膜片钳仪器的最新发展仍然比用于可溶性蛋白的常规药物筛选的通量低一个数量级，并且还需要昂贵的仪器、专门的细胞系和消耗品。对于现有的离子通道筛选方法，在信息质量、通量和成本方面存在很大差距。利布雷德公司正在开发一种替代的无细胞技术，用于使用人工细胞膜进行离子通道筛选。Librede正在申请的无细胞人工膜配方专利可以实现更高的通量和更低的消耗成本，同时需要更便宜的设备和训练有素的人员。Librede是由加州大学洛杉矶分校的研究人员和这项技术的发明者创立的。在这里提出的工作中，我们的目标是开发用于在我们的人工膜平台中测量和包装hERG通道的材料和方法。hERG是要筛选的重要离子通道，因为药物在hERG通道上的脱靶活性可导致心律失常和死亡;因此，所有候选药物，无论靶点如何，都必须针对与hERG的相互作用进行筛选。在这项工作中，我们将与加州大学洛杉矶分校的施密特小组合作，该小组首次在初步工作中演示了人工膜中hERG的测量。我们的目的是确定hERG与Librede人工膜平台的相容性，并确定优化hERG长期储存的条件，这些hERG与我们的膜阵列板包装在一起。最后，我们将通过在48膜阵列板上同时筛选hERG对已知通道阻断剂来演示我们的技术。这项工作是朝着我们降低离子通道筛选所需成本和专业知识的目标迈出的关键一步。公共卫生相关性：我们最近开发了一种新型的离子通道测量平台，该平台可以无限期地存储，商业运输，并且需要来自最终用户的非常少的输入来操作。我们的目标是验证这个平台与人类心脏离子通道hERG，以证明该技术的离子通道筛选的实用性。