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：
10337084
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 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10337084
关键词：
ADORA2A gene AMPA Receptors Address Adenosine Affinity Agonist Alpha Particles Axon Bacterial Polysaccharides Brain Carbamates Carrier Proteins Cell Culture Techniques Cells Central Nervous System Diseases Chemicals Chemistry Corpus striatum structure Cyclodextrins Devices Dextrans Diffuse Diffusion Dopamine Dopamine D2 Receptor Drug Targeting Electrochemistry Electron Transport Encapsulated Ethers Fluorescence Microscopy Generations Genetic 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 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 base 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 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一般工具可以对哺乳动物中的特定电路和单元进行监视和/或调制纯化学方法的大脑。我们最近披露了一个用于电压化学输送的聚合物平台对大脑中特定细胞类型的敏感染料（VSD）（单胺能神经元及其扩展），作为第一个非遗传系统的示例，可以靶向脑组织中高度亲脂性分子的靶向递送。我们有表明葡聚糖是一种细菌多糖，可以充当极性聚合物载体封装亲脂性VSD将其通过脑组织运输，并以特定的细胞类型部署它归巢配体的手段。拟议的研究旨在基于此概念验证示例并发展将亲脂性传感器和致动物/药物传递到大脑中特定细胞类型的一般平台。目标 1a我们将基于配体指导的酰基咪唑化学发展为A）开发无可接触的共价标记技术启用细胞类型的特异性靶向，而无需长期对系统的长期扰动。配体和b）共价固定在离子传输蛋白附近的电压传感器（AMPA接收器和多巴胺转运蛋白）以测量膜电位的局部变化。在AIM 1B中，我们将利用配体的药理作用通过将平台扩展到双毒剂靶向，这将使交付多巴胺受体D2激动剂专门针对表达D2的棘突神经元（D2-MSN），但不是纹状体中的多巴胺能轴突，通过腺苷受体A2A拮抗剂（D2-MSN标记）的均值。这将为细胞选择性药理学提供具有神经退行性潜在的治疗潜力的平台（例如帕金森氏病）和精神疾病。在AIM 2中，我们专注于A）优化高荧光VSD 使用Dextran平台的灵敏度和目标性； b）将靶向平台扩展到电压传感器启用新型成像方式，包括短波红外荧光显微镜和光声成像。在AIM 3中，我们将通过调整聚合物分子来系统地优化Dextran递送平台体重和替代模式。我们还将探索其他基于糖的聚合物作为输送系统大脑中的亲脂货物，包括环糊精和聚（苯乙烯 - 醚 - 三核）。这个五年的结果计划有望提供一个通用，优化的平台，用于传递亲脂传感器和执行器大脑中的特定细胞类型。化学靶向方法消除了对遗传操纵的需求从长远的角度来看，大脑将适用于人类和其他生物适用于遗传操作。