Next generation tools for imaging bacterial infection and its relationship to the immune system

用于成像细菌感染及其与免疫系统关系的下一代工具

基本信息

批准号：
10001362
负责人：
Mark A Sellmyer
金额：
$ 40.25万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-17 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10001362
关键词：
Address Animal Model Animals Antibiotic Resistance Antibiotic Therapy Antibiotics Appointment Bacteria Bacterial Infections Biological Markers Biological Phenomena Biomedical Research Biopsy Blood Brain Cell Communication Cells Characteristics Chemicals Chronic Clinical Clinical Services Communities Cystic Fibrosis Development Diagnosis Diagnostic Imaging Diffuse Discipline of Nuclear Medicine Disease Distant Engineering Enzymes Etiology Extracellular Domain Foundations Genetic Transcription Goals Granuloma Growth Heart Heterogeneity Histology Human Image Imaging Device Immune Immune response Immune system Immunohistochemistry Immunologic Monitoring In Vitro Infection Inflammation Inflammatory Intuition Laboratories Location Lung Malignant Neoplasms Measures Mentorship Microbe Modeling Modernization Molecular Monitor Mycobacterium tuberculosis Myositis Nitroreductases Organism Output Pathogenesis Pathologic Pathology Patients Pharmaceutical Preparations Pharmacology Physicians Physiological Plasmids Population Positron-Emission Tomography Pre-Clinical Model Process Proteins Publishing Pulmonary function tests Radiology Specialty Rattus Reagent Recording of previous events Reporter Reporting Research Research Personnel Resistance Rodent Sampling Biases Severities Signal Transduction Site Staphylococcal Protein A Stream Surface System Techniques Technology Testing Therapeutic Time Tissues Trimethoprim Uncertainty Validation Vertebral column Work bacterial resistance base bench to bedside cystic fibrosis patients draining lymph node global health health economics imager improved in vivo in vivo monitoring lung colonization macrophage migration next generation notch protein novel strategies novel therapeutic intervention pathogen professor programs radiologist radiotracer receptor response sensor small molecule spatiotemporal synthetic biology tenure track tool trafficking uptake

项目摘要

One of the great challenges of modern biomedical research is observing biologic phenomena in animals and people. An important example of this is our limited ability to monitor the course of bacterial infection. An image-based readout of a bacterial infection would allow differentiation of infection from other etiologies, a tailored duration of antibiotic treatment, and identification of antibiotic resistance suggesting an appropriate class of antibiotic. In addition to the clinical and population implications of improved monitoring of bacterial infections, basic researchers do not have simple tools to measure the immune response to the site of a bacterial infection. Again, imaging is suited to address this problem by facilitating in vivo monitoring over space and time. My work seeks to develop imaging-based chemical and synthetic biology technologies that illuminate bacterial pathogenesis, response to antibiotics, the development of antibiotic resistance, and bacterial interactions with the immune system. I propose complementary approaches to accomplish these goals using immune cells delivered into the blood stream that track bacterial biomarkers –including bacterial surface markers and bacterial enzymes– and using direct bacterial imaging with positron emission tomography (PET). These new approaches leverage concepts and techniques I have developed including “cell-cell proximity reporters”, protein destabilizing domains, and PET imaging based on the antibiotic trimethoprim (TMP). Advantages of using immune cells include the ability to generate multiplexed sensors and reporter outputs, transcriptional and enzymatic signal amplification, and regional assessment of immune cell trafficking. An advantage of direct bacterial imaging is the ability to image the bacterial load that does not depend on immune cell access to the infection. The primary objectives of this proposal are 1) to develop new receptors that can report the severity and species of bacterial infection in vivo. 2) to develop new classes of caged small molecules for monitoring immune cell-bacterial cell interactions using synthetic biology principles, and 3) to evaluate a new class of PET radiotracers I recently developed for imaging infection in a rat model of cystic fibrosis (CF) and measure bacterial radiotracer uptake in patients with CF before and after antibiotics. This work builds a foundation to monitor pathologic bacteria in vivo and spans from bench to bedside. I expect to provide sets of reagents to the scientific community including plasmids encoding receptors for a variety of bacteria, enzyme activated small molecules, and useful PET probes, all geared toward specific imaging of live bacteria.

现代生物医学研究的巨大挑战之一是观察生物动物和人类中的现象的一个重要例子是我们的监测能力有限。基于图像的细菌感染过程读数将允许区分感染与其他病因、定制抗生素治疗持续时间，以及抗生素耐药性的鉴定表明合适的抗生素类别。除了改进细菌监测的临床和人群影响之外感染，基础研究人员没有简单的工具来测量对感染的免疫反应同样，成像技术适合通过促进体内来解决这个问题。我的工作旨在开发基于成像的化学和时间。阐明细菌发病机制、对抗生素的反应、抗生素耐药性的发展以及细菌与免疫系统的相互作用。使用递送的免疫细胞实现这些目标的补充方法进入血液，追踪细菌生物标志物——包括细菌表面标志物和细菌酶——并使用正电子发射断层扫描直接细菌成像（PET）。这些新方法利用了我开发的概念和技术，包括 “细胞-细胞邻近育种”、蛋白质不稳定结构域以及基于使用免疫细胞的抗生素甲氧苄啶 (TMP) 的优点包括能够产生免疫细胞。多重传感器和报告输出、转录和酶信号放大、直接细菌成像的优点是免疫细胞运输的区域评估。能够对细菌负荷进行成像，而不依赖于免疫细胞对细菌的访问该提案的主要目标是 1) 开发能够报告感染的新受体。 2) 开发新的笼养小类。利用合成生物学监测免疫细胞-细菌细胞相互作用的分子原理，以及 3) 评估我最近开发的用于成像的新型 PET 放射性示踪剂囊性纤维化（CF）大鼠模型中的感染并测量细菌放射性示踪剂的摄取 CF 患者在使用抗生素之前和之后。这项工作为监测体内病理细菌奠定了基础，涵盖了我希望向科学界提供成套试剂，包括质粒编码多种细菌、活化小分子和酶的受体有用的 PET 探针，全部用于活细菌的特定成像。