Molecular probes to image and target the neurovascular unit in health and disease

摘要 内皮细胞(ECs)、星形胶质细胞和周细胞是神经血管单位(NVU)和 在血脑屏障(BBB)的形成和维持中起关键作用。这些细胞表达摄取和 外排膜转运体，调节中枢神经系统对分子、治疗药物和毒素的穿透。这个 在许多神经疾病中，血脑屏障和转运蛋白的功能可能被破坏。因此，发展 研究NVU细胞及其体内血脑屏障选择性转运特性的工具是翻译的关键优先事项 神经科学研究。我们已经发现了一组独特的小分子，可以选择性地 以极高的亲和力和特异性运输到内皮细胞、周细胞或星形胶质细胞的细胞质中。我们 有证据表明这些分子是通过膜转运蛋白进入细胞的，在每个细胞中选择性地表达 单元类型。我们推测这些分子可以用来作为活体动物和人类的探针。 成像，也用于特定细胞的药物输送。在这项提案中，我们的目标是确定准确的机制 建立了将这些分子用作细胞特异性药物的可行性 载体或作为放射性药物用于人体正电子发射断层扫描(PET)成像，最后 在阿尔茨海默病和中风模型中测试它们的体内特性。这个项目将改善我们的 了解跨血脑屏障的分子运输机制，并可能转化为选择性地 在健康和疾病中对NVU细胞进行成像和药物调节。

ABSTRACT Endothelial cells (ECs), astrocytes and pericytes are integral components of the neurovascular unit (NVU) and play critical roles in blood brain barrier (BBB) formation and maintenance. These cells express uptake and efflux membrane transporters that regulate CNS penetration of molecules, therapeutic drugs and toxins. The function of the BBB and transporters is likely disrupted in many neurological disorders. Thus, development of tools to study NVU cells and their properties of BBB selective transport in vivo is a key priority in translational neuroscience research. We have discovered a unique set of small molecules that can be selectively transported into the cytoplasm of either ECs, pericytes or astrocytes with exquisite affinity and specificity. We have evidence that these molecules enter cells through membrane transporters, selectively expressed in each cell type. We hypothesize that these molecules could be adapted as probes for intravital animal and human imaging and also for cell-specific delivery of drugs. In this proposal, we aim to identify the precise mechanisms of probe membrane transport in vivo; establish the feasibility of using these molecules as cell-specific drug carriers or as radiopharmaceuticals for human imaging with positron emission tomography (PET) and finally test their in vivo properties in models of Alzheimer's disease and stroke. This project will improve our understanding of molecular transport mechanisms across the BBB and may transform the ability to selectively image and pharmacologically modulate cells of the NVU in health and disease.