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Synthetic biology for controlled release

控制释放的合成生物学

基本信息

批准号：
9926117
负责人：
Andrew D Ellington
金额：
$ 34.53万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-04 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9926117
关键词：
Amino Acids Anabolism Automobile Driving Bacteria Base Pairing Biological Assay Blood Chronic Coupled Data Development Disease Drug Delivery Systems Drug Kinetics Elements Engineered Probiotics Ensure Enzymes Escherichia coli Feedback Gene Expression Health Human Human Microbiome Implant In Vitro Ingestion Injections Intervention Iowa Knowledge Laboratories Lead Levodopa Mathematics Mediating Messenger RNA Methods Mixed Function Oxygenases Modeling Mus Organism Output Parkinson Disease Pattern Pharmaceutical Preparations Physiologic pulse Positioning Attribute Probiotics Production Proteins RNA Regimen Solid Specific qualifier value System T7 RNA polymerase Testing Therapeutic Time Transgenic Mice Universities base controlled release design experimental study gut colonization metabolic engineering microbial microbiome microorganism mitopark mouse mouse model novel particle pharmacokinetics and pharmacodynamics pill pre-clinical synthetic biology transcription factor

项目摘要

Abstract: The prospects for the facile biosynthesis of drugs coupled with the manipulation of the human microbiome is fraught with therapeutic possibilities. However, the same caveats that exist for the delivery of drugs via ingestion or injection apply to the microbial delivery of drugs. In particular, a therapeutic regime for administration must be established that is efficacious but not harmful. For years, one means of ensuring the longer-term delivery of drugs in specified amounts has been to develop particles, pills, or patches that maintain the controlled or sustained release of drugs into the system. We propose a new paradigm for controlled release, in which controlled release is driven by controlled biosynthesis, which in turn relies on an underlying, modular regulatory mechanism. We establish a separate ‘engine’ for the expression of therapeutic cargoes, relying on the highly orthogonal T7 RNA polymerase (T7 RNAP), and develop a variety of circuits that lead to regulated gene expression in different patterns of therapeutic relevance, such as homeostatic production of constant concentrations of a drug (Aim 1). We then apply this ‘engine’ to the production of the amino acid L-DOPA in a known probiotic strain, E. coli Nissle (Aim 2). And then finally the controlled production circuitry in the probiotic species is introduced into mouse models in order to determine how programmed regulatory circuitry can impact the pharmacokinetics and pharmacodynamics of a drug in an organism (Aim 3). The strains are ultimately tested in a chronic progressive degenerative MitoPark mouse model of Parkinson’s disease currently being used in our collaborator’s laboratory at Iowa State University (Aim 3.3).

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