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Protein-folding-based in-vivo biosensors

基于蛋白质折叠的体内生物传感器

基本信息

批准号：
10176410
负责人：
Kevin W Plaxco
金额：
$ 18.75万
依托单位：
UNIVERSITY OF CALIFORNIA SANTA BARBARA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10176410
关键词：
Adopted Affinity Animal Model Antibiotics Antibodies Binding Biological Markers Biosensor Blood Blood Vessels Brain Chemicals Clinical Corpus striatum structure Couples Cyclosporine DNA Detection Development Devices Diagnostic Disease Dose Drug Kinetics Electrodes Electron Transport Elements Engineering Feedback Foundations Frequencies Glucose Goals Health Hormones Hour Immunization Immunomodulators Immunosuppressive Agents In Situ In Vitro Inferior Interleukin-6 Measurable Measurement Measures Medical Research Membrane Proteins Metabolic Methotrexate Methylene blue Molecular Molecular Conformation Molecular Target Monitor Nucleic Acids Oligonucleotides Outcome Output Oxidation-Reduction Performance Phage Display Pharmaceutical Preparations Physiological Precision therapeutics Preclinical Testing Progressive Disease Proteins Rattus Reporter Reporting Research Research Project Grants Resolution Risk Sepsis Signal Transduction Specificity Techniques Technology Testing Therapeutic Index Time Uncertainty Validation Whole Blood Work aptamer awake base body system clinical practice cytokine design diagnostic biomarker glucose monitor improved in vivo in vivo evaluation innovation minimally invasive nanobodies new technology novel strategies oxidation precision drugs prevent programs protein biomarkers protein folding real time monitoring receptor response sensor sensor technology small molecule success temporal measurement

项目摘要

Summary. Our overarching research goal is the development of a minimally invasive, receptor-based technology able to monitor the concentration of effectively any specific molecule (irrespective of its chemical reactivity) in the living body. To this end, we have already demonstrated the ability of electrochemical, aptamer-based (E-AB) sensors to monitor a range of drugs and metabolites in situ in the blood vessels and brain of awake, freely moving rats with seconds resolution and measurement durations of hours. A potentially significant limitation of the platform, however, is its reliance on nucleic acid aptamers, the limited chemical complexity of which will no doubt ultimately restrict the number of targets amenable to detection using the approach. In response, we propose here to develop the first sensors in this class that instead employ proteins as their recognition elements. Specifically, we propose two aims that will significantly de-risk the development of protein-folding-based electrochemical sensors, setting the stage for their development as a powerful new approach to molecular monitoring. First, we will expand beyond the single, proof-of-principle example (a sensor fabricated using the FynSH3 domain as our receptor) we have realized to date to sensors against three additional, clinically important targets (the sepsis-diagnostic cytokine IL-6, the chemotherapeutic and immune modulator methotrexate, and the immunosuppressant cyclosporine) as evidence that our design strategy is general. Second, we will adapt these sensors, which we have already shown are capable of multi-hour performance in undiluted whole blood in vitro, to the more challenging measurement conditions found in vivo. If successful, the R21-scale project described here will lay the foundation for an R01-level research program that couples this technology with in vitro and in vivo protein selection to create sensors supporting the continuous, real time measurement of many clinically important molecules, including narrow-therapeutic-index drugs and protein biomarkers indicative of the status of many grievous, rapidly progressive diseases.

总结。我们的首要研究目标是开发一种微创的，基于受体的