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

分子探针对健康和疾病中的神经血管单元进行成像和靶向

基本信息

批准号：
10545711
负责人：
Jaime Grutzendler
金额：
$ 60.62万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10545711
关键词：
Address Affinity Alzheimer&apos s Disease Alzheimer&apos s disease model Animals Astrocytes Blood Blood - brain barrier anatomy Blood Cells Brain Brain Ischemia Brain imaging CRISPR/Cas technology Calcium Capillary Endothelial Cell Cell Communication Cells Cellular Structures Chemicals Complex Cytoplasm Data Databases Development Diagnostic Disease Drug Carriers Drug Compounding Drug Delivery Systems Electroporation Endothelial Cells Future Health Homeostasis Human Hybrids Image In Vitro Ions Knockout Mice Knowledge Label Libraries Maintenance Membrane Transport Proteins Molecular Molecular Probes Movement Mus Nerve Degeneration Neurodegenerative Disorders Neurosciences Research Nutrient Organic Cation Transporter Pathogenesis Pathology Pattern Penetration Pericytes Permeability Pharmaceutical Preparations Plasmids Play Positron-Emission Tomography Property RNA Radiopharmaceuticals Regulation Resolution Role Route Specificity Stroke Structure Testing Therapeutic Therapeutic Agents Toxin Tracer Translational Research Transmembrane Transport Transport Process Water Work animal imaging blood-brain barrier function brain cell brain surgery cell type cellular imaging chemical synthesis experimental study fluorophore functional group human imaging improved in utero in vivo in vivo optical imaging interdisciplinary approach mouse model nervous system disorder neurovascular unit novel optical imaging overexpression pharmacologic radiotracer screening selective expression small molecule small molecule libraries solute targeted delivery tool tool development trafficking transcriptome translational neuroscience two-photon uptake

项目摘要

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.

抽象的内皮细胞 (EC)、星形胶质细胞和周细胞是神经血管单元 (NVU) 的组成部分在血脑屏障（BBB）的形成和维持中发挥关键作用。这些细胞表达摄取和调节中枢神经系统分子、治疗药物和毒素渗透的外排膜转运蛋白。这在许多神经系统疾病中，血脑屏障和转运蛋白的功能可能会受到干扰。因此，发展研究 NVU 细胞及其体内 BBB 选择性转运特性的工具是转化中的一个关键优先事项神经科学研究。我们发现了一组独特的小分子，可以选择性地以精细的亲和力和特异性转运到 EC、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通过膜转运蛋白进入细胞，并在每个细胞中选择性表达细胞类型。我们假设这些分子可以用作活体动物和人类的探针成像以及细胞特异性药物输送。在本提案中，我们的目标是确定精确的机制探针膜在体内的转运；确定使用这些分子作为细胞特异性药物的可行性载体或作为用于正电子发射断层扫描（PET）人体成像的放射性药物，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 BBB 的分子转运机制，并可能改变选择性地转运的能力对健康和疾病状态下的 NVU 细胞进行成像和药理学调节。