Programmable Probiotics for Cancer

可编程益生菌治疗癌症

基本信息

批准号：
9189187
负责人：
Tal Danino
金额：
$ 24.9万
依托单位：
COLUMBIA UNIV NEW YORK MORNINGSIDE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9189187
关键词：
Address Adenocarcinoma Apoptotic Bacteria Bacterial Luciferases Behavior Binding Biological Markers Cancer Model Cell Line Cells Cleaved cell Colorectal Colorectal Cancer Computer Simulation Cytolysis Data Detection Development Diagnosis Diagnostic Dimensions Dose-Limiting Engineering Environment Enzyme-Linked Immunosorbent Assay Fluorescence Genes Genetic Genetically Engineered Mouse Growth Health Histocompatibility Testing Homing Hour Human Human body Image Immune response Immunocompetent In Vitro Infection Injectable Intestines Laboratories Luciferases MDA MB 435 Malignant Neoplasms Measurement Measures Membrane Proteins Mentors Metastatic Neoplasm to the Liver Methods Microbe Microfluidic Microchips Microfluidics Microscopy Modeling Monitor Mus Necrosis Oral Oral Administration Oxygen Paper Peptides Pharmaceutical Preparations Phase Polyps Population Population Density Prevalence Probiotics Production Research Ribosomes Science Sensitivity and Specificity Specificity Staging Surface Technology Testing Therapeutic Time Tissues Toxic effect Translating Translations Urine Weight base clinical application clinically relevant design dosage engineering design imaging system improved in vivo in vivo imaging intravenous administration mathematical model microbial microbiome mouse model optimism pathogen peptide drug pre-clinical promoter receptor subcutaneous synthetic biology targeted treatment time use translational medicine tumor tumor progression uptake vector

项目摘要

DESCRIPTION (provided by applicant): Over the past decade, the long-held view of bacteria as pathogens has been transformed by microbiome data revealing an astounding prevalence of microbes within the human body. These bacteria exist not only in well- known regions such as the intestines, but also in a multitude of tissue types including tumors. Given this prevalence, microbes represent a natural platform for the development of diagnostics and therapies engineered to sense their environment and deliver drugs to tumors. Current & Mentored Research: Our preliminary results have shown that oral delivery of probiotic bacteria can colonize colorectal liver metastases and enzymatically cleave an injected substrate that can be detected in the urine (Danino et al., Science Translational Medicine, in revision). Building upon this result to improve sensitivity and specificity, we will engineer a gene circuit to lyse at a threshold population density within the tumor environment and release a urine diagnostic peptide. Circuit parameters will be predicted by mathematical modeling, characterized by microfluidic measurements, and experimentally tuned by genetic copy number and ribosome binding strengths to optimize for detection of the diagnostic peptide in mouse models. Independent Phase Research: Following initial characterization of the engineered diagnostic circuit, we will assess colonization in more realistic orthotopic and genetically engineered mouse models of colorectal cancer. We will determine earliest stages at which bacteria colonization occurs and simultaneously measure diagnostic peptide concentrations in the urine. We will target our probiotics with tumor-homing peptides, express pro- apoptotic peptides as therapeutics, and monitor progression of tumors as a function of time. Altogether, the programmable probiotic platform will allow for more sophisticated microbial diagnostics and therapeutics for cancer and establish an engineering framework for in vivo applications for synthetic biology.

描述（由适用提供）：在过去的十年中，细菌作为病原体的长期视图通过微生物组数据转化，揭示了人体内部微生物的惊人流行。这些细菌不仅存在于诸如肠道之类的知名区域，而且存在于包括肿瘤在内的多种组织类型中。鉴于这种患病率，微生物代表了开发诊断和疗法的自然平台，该平台旨在感知环境并将药物运送到肿瘤。当前和指导的研究：我们的初步结果表明，益生菌的口服递送可以在尿液中检测到可以检测到的彩色彩色肝转移，并在酶上清除注射的底物（Danino等，Science Translational Medicine，in Revision）。在这一结果以提高敏感性和特异性的基础上，我们将设计基因回路以在肿瘤环境中的阈值种群密度下裂解并释放尿液诊断肽。电路参数将通过数学建模来预测，其特征是微流体测量值，并通过遗传拷贝数和核糖体结合强度进行实验调节，以优化以检测小鼠模型中诊断肽。独立的阶段研究：在对工程诊断电路的初始表征之后，我们将评估更现实的原位和基因工程性小鼠结直肠癌模型的定殖。我们将确定发生细菌定植的最早阶段，并轻松测量尿液中的诊断肽浓度。我们将用肿瘤毒性肽靶向益生菌，表达凋亡肽作为治疗，并根据时间的函数监测肿瘤的进展。总体而言，可编程益生菌平台将允许对癌症进行更复杂的微生物诊断和治疗，并为合成生物学的体内应用建立工程框架。