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Development of an ICMT Supported Membrane Sensor

ICMT 支持的薄膜传感器的开发

基本信息

批准号：
7350885
负责人：
DAVID H THOMPSON
金额：
$ 37.03万
依托单位：
PURDUE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-03-01 至 2010-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7350885
关键词：
Active Biological Transport Address Adenosylhomocysteinase Adsorption Affinity Amino Acid Motifs Amino Acids Analytical Chemistry Antibodies Architecture Area Binding Biochemical Reaction Biochemistry Biological Biological Assay Biological Models C-terminal Cell membrane Cells Chemotherapy-Oncologic Procedure Chimeric Proteins Class Computer Systems Development Confocal Microscopy Coupled Cysteine Data Deposition Detection Development Devices Diffusion Dilution Techniques Dimensions Disease Disulfides Elements Endoplasmic Reticulum Engineering Enzymes Epitopes Equilibrium Event Exposure to Facility Construction Funding Category Family Film Flowcharts Fluorescence Fluorescence Recovery After Photobleaching Future Generations Goals Green Fluorescent Proteins Hemagglutinin Histidine Homocysteine Homocystine Hydrolase Hydrolysis Immunofluorescence Immunologic Integral Membrane Protein Interference Microscopy Intervention Ionic Strengths Lateral Lead Libraries Link Lipids Liposomes Localized Maintenance Mattresses Measures Mechanics Mediating Membrane Membrane Proteins Methods Methylation Micelles Mission Modeling Molecular Molecular Conformation Molecular Weight Monitor Monte Carlo Method Nitrilotriacetic Acid Nutrient Oncogenic Operative Surgical Procedures Outcome Performance Pharmaceutical Preparations Phase Polyethylene Polyethylene Glycols Polyethylenes Post-Translational Protein Processing Preclinical Drug Evaluation Principal Investigator Production Property Proteins Range Rate Reaction Refractory Reporter Research Research Personnel Role playing therapy Saccharomyces cerevisiae Scheme Side Signal Transduction Silicon Dioxide Solid Solutions Structure Subarachnoid Hemorrhage Sulfhydryl Compounds Surface System Techniques Technology Temperature Testing Therapeutic Agents Thick Time Validation Variant Vesicle base cell transformation chemotherapeutic agent concept density design detector drug development drug discovery extracellular farnesyltranstransferase fluorophore functional group high throughput screening improved inhibitor/antagonist innovation isoprenylcysteine carboxylmethyltransferase member milligram multidisciplinary novel novel strategies novel therapeutics pathogen prevent programs protein expression protein farnesyltransferase protein function ras Proteins receptor reconstitution research study response sensor theories tool tumor vapor

项目摘要

The long term goal of this project is the development of multi-element membrane-based sensor arrays on a single chip for high-throughput, parallel sensing of therapeutic agent candidates acting on specific membrane protein targets. Successful development of this sensing technology can lead to accelerated drug discovery targeted to membrane proteins involved in a variety of diseases. We will develop a stabilized asymmetric membrane structure containing isoprenylcysteine carboxylmethyltransferase (ICMT) in this project as a potential new tool for drug discovery in cancer chemotherapy. ICMT is a membrane protein in the endoplasmic reticulum responsible for the carboxylmethylation of -CaaX motif proteins, including the Ras signal transduction proteins. This membrane sensor architecture will enable the detection of Icmt-mediated methylation of the model substrate N-acetylfarnesylcysteine as a change in fluorescence emission due to the coupled cleavage of a disulfide-linked molecular beacon. Sensors developed from these asymmetric structures will provide a direct indication of a drug candidate's ability to inhibit methylation catalyzed by Icmt. This approach will serve as a powerful tool for screening drug libraries for lead compounds that are likely to inhibit the methylation of cellular oncogenic Ras proteins. Discovery and development of these compounds are important because inhibition of Ras carboxylmethylation promotes not only the mislocalization of the Ras proteins, but also inhibits the ability of Ras to transform cells. ICMT is an excellent model system for development of this membrane-based sensor because many well-characterized substrates exist to provide data validation. These substrates will be used as tools to develop a high-throughput screening approach that may lead to improved chemotherapeutic agents for refractory tumors. Subsequent phases of the project will address the design, fabrication, characterization, and validation of multi-element sensor arrays on an optically transparent substrate. A multidisciplinary team approach will be used, combining expertise in biochemistry, materials synthesis and characterization, analytical chemistry, and theory to achieve the target supported membrane device. Future extension of this detector array concept could have far reaching potential for accelerating the discovery of new therapeutic agents targeted to many other classes of membrane-associated proteins.

该项目的长期目标是开发基于薄膜的多元件传感器阵列