Diversity Supplement_Integrated three-dimensional (3D) microscopy for a spatial pharmacology atlas of macromolecular drugs in the tissue microenvironment

项目摘要 该项目的目标是开发一种新的组织分析方法，允许单细胞分辨 大分子药物在空间背景下的药代动力学(PK)和药效学(PD)谱 健康和疾病状态下器官特有的组织微环境。使用集成的3D 显微镜下，我们将1)绘制大分子药物的血管系统和跨血管传输图；2)图像 具有多种细胞类型的大分子药物在组织微环境中的分布和相互作用； 3)在分子水平上确定亚微环境区域细胞对大分子药物的反应。 这种高分辨率的3D多路显微技术将推进药学领域的空间药理学 通过绘制大分子药物的运输、分布和生物作用的图谱来实现科学 在组织范围、细胞和分子水平的组织标本中。这些地图将提供对 大分子药物的血管转运、药物-细胞相互作用和各种细胞的生物反应 对器官不同亚微环境区域的药物。地图的集合，空间地图集 药理学，将成为大分子研究和临床前开发的坚实标准参考 毒品。

Project Summary The goal of this project is to develop a new tissue assay method that permits single-cell resolution pharmacokinetics (PK) and pharmacodynamics (PD) profiling of macromolecular drugs in the spatial context of the organ-specific tissue microenvironment in both healthy and diseased states. With the integrated 3D microscopy, we will 1) map blood vasculature and transvascular transport of macromolecular drugs; 2) image the distribution and interaction of macromolecular drugs with multiple cell types in the tissue microenvironment; 3) determine cellular responses to macromolecular drugs in sub-microenvironment regions at the molecular level. This high-resolution 3D multiplex microscopy method will advance “Spatial Pharmacology” in the pharmaceutical sciences by enabling the mapping of the transport, distribution, and biological actions of macromolecular drugs in tissue specimens at the tissue-wide, cellular and molecular levels. The maps will provide new insights into transvascular transport of macromolecular drugs, drug-cell interactions, and biological responses of various cells to drugs in different sub-microenvironment regions of an organ. The collection of the maps, The Atlas of Spatial Pharmacology, will be a solid standard reference in the research and preclinical development of macromolecular drugs.