Programmable Probiotics for Cancer

可编程益生菌治疗癌症

基本信息

批准号：
9252421
负责人：
Tal Danino
金额：
$ 22.07万
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/9252421
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 Diagnostic Specificity Dimensions Dose-Limiting Engineering Environment Enzyme-Linked Immunosorbent Assay Fluorescence Genes Genetic Genetically Engineered Mouse Growth Health Homing Hour Human Human body Immune response Immunocompetent In Vitro Inbred BALB C Mice Infection Injectable Intestines Intravenous 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 Sensitivity and Specificity Specificity Surface Technology Testing Therapeutic Therapeutic Uses Time Tissues Toxic effect Translating Translational Research Translations Urine Weight base clinical application clinically relevant design dosage imaging system improved in vivo in vivo imaging system intravenous administration mathematical model microbial microbiome mouse model optimism pathogen peptide drug pre-clinical programs promoter public health relevance 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（由申请人提供）：在过去的十年中，微生物组数据改变了人们长期以来对细菌作为病原体的看法，这些数据揭示了人体内微生物的惊人流行，这些细菌不仅存在于众所周知的地区，例如：鉴于这种普遍性，微生物代表了开发旨在感知其环境并向肿瘤输送药物的诊断和治疗的天然平台。我们的初步结果表明，口服益生菌可以在结直肠肝转移瘤中定殖，并酶切可在尿液中检测到的注射底物（Danino 等人，《科学转化医学》，在此结果的基础上提高灵敏度）。和特异性，我们将设计一个基因电路，在肿瘤环境中以阈值群体密度裂解并释放尿液诊断肽。电路参数将通过数学模型进行预测，并通过微流体测量进行表征。通过基因拷贝数和核糖体结合强度进行实验调整，以优化小鼠模型中诊断肽的检测。独立阶段研究：在工程诊断电路的初步表征之后，我们将评估更真实的原位和基因工程小鼠结直肠模型中的定植。我们将确定细菌定植发生的最早阶段，并同时测量尿液中的诊断肽浓度。我们将用肿瘤归巢肽来靶向益生菌，表达促凋亡肽作为治疗剂，总而言之，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。