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

• 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
• 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

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 动物和人身上的现象。一个重要的例子是我们的监控能力有限 细菌感染的过程。基于图像的细菌感染读数将允许 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。 除了改善细菌监测对临床和人群的影响外， 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 细菌感染的部位。同样，成像技术可以通过促进体内成像来解决这个问题。 空间和时间上的监控。我的工作旨在开发基于成像的化学和 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。我 提出使用递送的免疫细胞来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 （宠物）。这些新方法利用了我开发的概念和技术，包括 “细胞-细胞邻近记者”、蛋白质不稳定结构域和基于 抗生素甲氧苄啶（TMP）。使用免疫细胞的优点包括能够产生 多重传感器和报告输出、转录和酶信号放大、 以及免疫细胞贩运的区域评估。直接细菌成像的优点是 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 感染。该提案的主要目标是 1) 开发能够报告的新受体 体内细菌感染的严重程度和种类。 2）开发新类别的笼养小动物 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 长凳到床边。我希望向科学界提供成套试剂，包括 编码多种细菌受体、酶激活小分子的质粒，以及 有用的 PET 探针，全部用于活细菌的特定成像。