Optical small animal imaging unit for quantification of bacterial infections

描述（由申请人提供）：细菌感染在全球范围内造成了昂贵的健康负担，多重耐药细菌的惊人增加加剧了这一负担，其中许多感染发生在泌尿生殖道。泌尿生殖道感染（UTI）每年困扰全世界莫尔2.5亿成人和儿童。然而，负责开发下一类抗生素的制药公司没有工具来定量和纵向地监测同一小动物体内细菌器官负荷，而无需收获器官。因此，无法实时研究病原菌的生命周期和新型抗生素的功效。发光细菌通常用作小动物体内细菌感染的光学成像工具，然而，光被组织强烈衰减，并且测量的信号取决于（i）细菌的空间位置，（ii）异质光学组织特性，以及（iii）动物的大小和形状。目前还没有商业工具可以有效地解决这些负担，以准确地体内定量和定位组织内的细菌密度分布。因此 所提出的工作旨在开发用于光学成像系统的集成硬件和软件单元，其（i）将直接计算活动物中的细菌负荷，以及（ii）将其瞬时地与动物的解剖结构共配准。这一任务将通过一种新型的体外光学校准器、一种符合体型的动物模型和一个数字化的小鼠图谱来完成。校准器模拟光学组织特性，并且因此将使得能够量化 细菌的光产率。光学透明且符合体形的动物模具为动物提供固定的几何形状，同时实现（i）与数字小鼠图谱的共配准和（ii）构建用于光传播模型的异质光学性质图。在目标1中，将开发基于器官概率图（OPM）的新型数字小鼠图谱，以确定细菌感染的准确体内解剖位置。在目标2中，体内细菌密度（每组织体积的菌落形成单位）将为 在尿路感染的动物模型中测定。所提出的成像单元将（i）通过允许纵向地实时监测同一动物中的细菌感染来缩短体内研究，（ii）提供即时解剖参考，以及（iii）降低成本 对于需要光学报告成像和解剖参考的研究人员来说，这是一个障碍，而不需要使用额外的和昂贵的解剖成像方式，如磁共振成像（MRI）。该项目的成功完成将有助于成像单元的商业化，并将立即应用于制药行业，以快速开发新型抗生素。长期目标是将该装置的效用扩展到 其他需要量化生物发光目标的领域，如神经生物学、肿瘤学和干细胞研究。

DESCRIPTION (provided by applicant): Bacterial infections impose a costly health burden worldwide which is compounded by the alarming increase of multi-drug resistant bacteria, and many of these infections are in the urogenital tract. Urogenital tract infections (UTI) afflict mor than 250 million adults and children worldwide each year. However, pharmaceutical companies tasked with developing the next class of antibiotics do not have the tools to monitor in vivo bacterial organ burden quantitatively and longitudinally in the same small animal without harvesting organs. Consequently, the life cycle of pathogenic bacteria and the efficacy of novel antibiotics cannot be studied in real-time. Luminescent bacteria are commonly used as a tool for optical imaging of in vivo bacterial infections in small animals, however, light is strongly attenuated by tissue and the measured signal is dependent on (i) the spatial location of bacteria, (ii) the heterogeneous optical tissue properties, and (iii) the animal's size and shape. There is currently no commercial tool that effectively addresses these burdens for accurate in vivo quantification and localization of the bacterial density distribution inside tissue. Therefore, the proposed work is aimed at developing an integrated hardware and software unit for optical imaging systems that (i) will directly calculate the bacterial burden in a living animal and (ii) instantaneously co-register it to the animal's anatomy. This task will be accomplished through a novel in vitro optical calibrator, a body-shape-conforming animal mold, and a digital mouse atlas. The calibrator mimics optical tissue properties and, thus, will enable the quantification of the bacterial light yield. The optically transparent and body-shape-conforming animal mold provides a fixed geometry for the animal while enabling (i) the co-registration to the digital mouse atlas and (ii) the construction of a heterogeneous optical property map for a light propagation model. In Aim 1, a novel digital mouse atlas based on an Organ Probability Map (OPM) will be developed to determine the accurate in vivo anatomical location of bacterial infection. In Aim 2, the in vivo bacterial density (colony forming units per tissue volume) will be determined in an animal model of urinary tract infection. The proposed imaging unit will (i) shorten in vivo studies by allowing real-time monitoring of bacterial infections in the same animal longitudinally, (ii) provide an instantaneous anatomical reference, and (iii) lower the cost barrier for researchers needing both optical reporter imaging and an anatomical reference without using an additional and expensive anatomical imaging modality like magnetic resonance imaging (MRI). The successful completion of the proposed project will help to commercialize the imaging unit and will find immediate application in the pharmaceutical industry for rapid development of novel antibiotics. The long-term goal is to extend the unit's utility to a number of other fields needing to quantify bioluminescent targets such as in neurobiology, oncology, and stem cell research.