Chemical Targeting of Sensors and Pharmacological Probes in the Brain

大脑中传感器和药理学探针的化学靶向

基本信息

批准号：
10555221
负责人：
DALIBOR SAMES
金额：
$ 56.31万
依托单位：
COLUMBIA UNIV NEW YORK MORNINGSIDE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10555221
关键词：
ADORA2A gene AMPA Receptors Adenosine Affinity Agonist Axon Bacterial Polysaccharides Brain Carbamates Carrier Proteins Cell Culture Techniques Cells Central Nervous System Diseases Chemicals Chemistry Compensation Corpus striatum structure Cyclodextrins DRD2 gene Devices Dextrans Diffusion Dopamine Dopamine D2 Receptor Drug Targeting Electrochemistry Electron Transport Encapsulated Ethers Fluorescence Microscopy Generations Genetic Glutamate Receptor Glutamates Goals Homing Human Hydrophobicity Image Imidazole Immobilization Individual Indocyanine Green Ion Transport Label Length Ligands Mammals Measurement Measures Membrane Potentials Membrane Proteins Mental disorders Methods Molecular Molecular Target Molecular Weight Monitor Nature Nerve Degeneration Neurobiology Neurons Optics Organism Outcome Parkinson Disease Pattern Pharmaceutical Preparations Pharmacology Photons Physiology Play Polymers Population Porphyrins Positioning Attribute Printing Property Receptor Signaling Research Role SCH 58261 Schizophrenia Short Waves Signal Transduction Styrenes Surface Synapses System Techniques Testing Therapeutic Tissue imaging Tissues Trehalose Universities antagonist autism spectrum disorder biological systems brain tissue cell type chromophore design dopamine transporter genetic manipulation hydrophilicity imaging modality imaging probe improved interest lipophilicity microscopic imaging multidisciplinary non-genetic novel particle pharmacologic photoacoustic imaging programs protein biomarkers prototype receptor ropinirole sensor targeted delivery tool voltage voltage sensitive dye

项目摘要

SUMMARY Chemical Targeting of Sensors and Pharmacological Probes in the Brain There are no general tools that enable monitoring and/or modulation of specific circuits and cells in the mammalian brain by purely chemical means. We have recently disclosed a polymer platform for chemical delivery of voltage sensitive dyes (VSDs) to specific cell types in the brain (monoaminergic neurons and their extensions), as a first example of a non-genetic system enabling targeted delivery of highly lipophilic molecules in brain tissue. We have shown that dextran, a bacterial polysaccharide, can function as a polar polymer carrier which dynamically encapsulates the lipophilic VSD to carry it through brain tissue and deploy it at a specific cell type of interest by the means of a homing ligand. The proposed research aims to build on this proof-of-concept example and develop a general platform for delivery of lipophilic sensors and actuators/drugs to specific cell types in the brain. In Aim 1A we will develop traceless covalent labeling techniques based on ligand-directed acyl imidazole chemistry to a) enable cell-type specific targeting without long-term perturbation of the system by pharmacological effects of the ligand, and b) covalently immobilize voltage sensors in the vicinity of ion transporting proteins (AMPA receptor and dopamine transporter) to measure local changes of membrane potential. In Aim 1B, we will leverage the pharmacological effects of the ligands by extending the platform to dual-drug targeting which will enable delivery of dopamine receptor D2 agonists specifically to D2-expressing medium spiny neurons (D2-MSNs), but not dopaminergic axons in the striatum, by the means of an adenosine receptor A2A antagonist (a D2-MSN marker). This will provide a platform for cell selective pharmacology with therapeutic potential for neurodegenerative (e.g. Parkinson’s disease) and psychiatric disorders. In Aim 2 we focus on a) optimization of fluorescent VSDs for high sensitivity and targetability using the dextran platform; and b) extension of the targeting platform to voltage sensors enabling novel imaging modalities including short wave infrared fluorescence microscopy and photoacoustic imaging. In Aim 3 we will systematically optimize the dextran delivery platform by tuning the polymer molecular weight and substitution pattern. We will also explore other saccharide-based polymers as delivery systems for lipophilic cargo in the brain, including cyclodextrins and poly(styrene-ether-trehalose). The outcome of this 5-year program promises to provide a general and optimized platform for delivery of lipophilic sensor and actuators to specific cell types in the brain. The chemical targeting approach eliminates the need for genetic manipulation of the brain and thus will be, in a long-term perspective, applicable to humans and other organisms not readily adaptable for genetic manipulations.

概括大脑中传感器和药理学探针的化学靶向没有通用工具可以监测和/或调节哺乳动物的特定电路和细胞我们最近公开了一种用于化学传递电压的聚合物平台。对大脑中特定细胞类型（单胺能神经元及其延伸）敏感的染料（VSD），作为第一个我们有一个能够在脑组织中定向输送高亲脂性分子的非遗传系统的例子。研究表明，葡聚糖（一种细菌多糖）可以作为极性聚合物载体，动态地封装亲脂性 VSD，使其穿过脑组织，并将其部署在感兴趣的特定细胞类型上拟议的研究旨在建立在这个概念验证示例的基础上并进行开发。 In Aim 是一个将亲脂性传感器和执行器/药物输送到大脑中特定细胞类型的通用平台。 1A 我们将开发基于配体定向酰基咪唑化学的无痕共价标记技术，以a) 能够实现细胞类型特异性靶向，而不会因药物的药理作用而对系统造成长期干扰配体，b) 将电压传感器共价固定在离子转运蛋白（AMPA 受体）附近和多巴胺转运蛋白）来测量膜电位的局部变化。在目标 1B 中，我们将利用通过将平台扩展到双药物靶向来实现配体的药理作用，从而实现递送多巴胺受体 D2 激动剂特异性作用于表达 D2 的中型多棘神经元 (D2-MSN)，但不通过腺苷受体 A2A 拮抗剂（D2-MSN 标记），纹状体中的多巴胺能轴突。这将为细胞选择性药理学提供一个平台，具有治疗神经退行性疾病（例如神经退行性疾病）的潜力。在目标 2 中，我们重点关注 a) 针对高水平的荧光 VSD 的优化。使用葡聚糖平台的灵敏度和靶向性；和 b) 将靶向平台扩展到电压传感器实现新型成像模式，包括短波红外荧光显微镜和光声在目标 3 中，我们将通过调整聚合物分子来系统地优化葡聚糖递送平台。我们还将探索其他基于糖的聚合物作为递送系统。大脑中的亲脂性物质，包括环糊精和聚（苯乙烯-醚-海藻糖）这五年的成果。该计划有望提供一个通用且优化的平台，用于将亲脂性传感器和执行器传递给化学靶向方法消除了对大脑中特定细胞类型的基因操作的需要。大脑，因此从长远来看，将适用于人类和其他不易实现的生物体适合基因操作。