Molecular tools to decipher communication across the blood-brain barrier

破译跨血脑屏障通讯的分子工具

基本信息

批准号：
10704542
负责人：
Andrew Chris Yang
金额：
$ 40.38万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-14 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10704542
关键词：
Adult Aging Amino Acids Binding Bioinformatics Biological Models Biology Blood Blood - brain barrier anatomy Blood Circulation Blood Proteins Brain Brain Diseases Carrier Proteins Catalogs Cause of Death Caveolins Cell surface Cells Chemicals Chemistry Clathrin Communication Contact Tracing Cues Dedications Discipline Disease Doctor of Philosophy Drug Delivery Systems Endothelial Cells Endothelium Engineering Exposure to Faculty Financial Support Frustration Functional disorder Funding Goals Health Health protection Immune Inflammatory Institution Label Leadership Learning Licensing Ligands Ligase Mediating Mentors Mentorship Methods Microglia Molecular Mus Nature Nervous System Physiology Neuroimmune Neurons Neurosciences Observational Study Paper Pathway interactions Perfusion Peripheral Permeability Physiological Plasma Plasma Cells Plasma Proteins Positioning Attribute Postdoctoral Fellow Principal Investigator Printing Property Protein Secretion Proteins Proteome Proteomics Reporting Research Research Project Grants Route Secure Signal Transduction Site Students Support System T-Lymphocyte Techniques Therapeutic Tight Junctions Tracer Training Transferrin Universities blood-brain barrier crossing blood-brain barrier permeabilization brain health career cell motility cell type effective therapy faculty mentor in vivo innovation intercellular communication migration neuroinflammation new therapeutic target protein transport receptor recruit response senior faculty synthetic biology targeted delivery tool transcytosis transmission process undergraduate student

项目摘要

Project Summary/Abstract The blood-brain barrier (BBB) maintains brain health by protecting the brain from the bloodstream. These barrier properties frustrate the treatment of nearly all brain disorders, representing one of the largest challenges in neuroscience and drug delivery. Yet, intriguingly, recent studies have discovered a variety of surprising peripheral influences on brain function, hinting at the existence of underappreciated modes of communication across the BBB. Indeed, while canonical BBB properties, such as paracellular tight junctions and minimal caveolin-mediated transcytosis, have been established via a handful of standard tracers, it remains unclear whether these tracers fully represent the BBB’s physiological interactions with and permeability to the thousands of circulating proteins and cells it is constantly exposed to. By developing methods to tag and track the blood plasma proteome, I recently observed an unexpected degree and diversity of protein transport into the healthy adult brain. Thus, I hypothesize that brain health is maintained not just by BBB impermeability—but by specific routes of blood-to-brain communication actively facilitated by the BBB. Specifically, I propose that there are three logical routes for how peripheral information is communicated across the healthy BBB: the direct transport of proteins into the brain; the responsive relay of proteins made by the BBB into the brain; and the BBB-licensed migration of peripheral immune cells into the brain. By combining proteome tagging techniques with bioorthogonal chemistries, each proposed aim explores one independent route to systematically reveal the identities and mechanisms of the signals transmitted via the healthy BBB. I will begin by creating a first catalog of plasma proteins that directly cross the BBB and quantifying their permeabilities (Aim 1). I will subsequently characterize a new BBB relay function by deducing the signals the BBB secretes into the brain in response to peripheral cues (Aim 2). Lastly, I will elucidate neuroimmune surveillance by determining the BBB sites and molecules enabling healthy immune cell migration into the brain (Aim 3). Together, these studies will expand our understanding of how the BBB maintains brain health and enable new studies exploring the neurological functions of BBB-permeable proteins and cells in health, aging, and disease. Our results will also provide a comprehensive set of functional targets to enhance drug delivery to the brain, reveal new mechanisms to understand and blunt neuroinflammation, and generate innovative tools to decipher intercellular communication for broad use across disciplines.

项目摘要/摘要血脑屏障（BBB）通过保护大脑免受血液的影响来维持大脑健康。这些屏障特性挫败了几乎所有脑部疾病的治疗，代表最大的脑部疾病之一神经科学和药物输送方面的挑战。然而，有趣的是，最近的研究发现了各种各样的令人惊讶跨BBB的通信。确实，虽然规范的BBB特性，例如细胞细胞紧密连接和最小的小窝蛋白介导的转胞膜作用是通过少数标准示踪剂建立的尚不清楚这些示踪剂是否完全代表了BBB与和对数千种循环蛋白和细胞的渗透性不断暴露于。通过发展标记和跟踪血浆蛋白质组的方法，我最近观察到意外程度和多样性蛋白质转运到健康的成年大脑中。我假设，不仅可以维持大脑健康 BBB的不渗透性 - 但是通过BBB积极支持的血液到脑通信的特定途径。具体来说，我建议有三种逻辑途径用于如何传达外围信息跨越健康的BBB：将蛋白质直接转运到大脑中；由 BBB进入大脑；以及BBB许可的外周免疫细胞迁移到大脑中。通过组合蛋白质组标记技术带有生物正交化学，每个拟议的目标都探索一个独立的系统地揭示通过健康BBB传输的信号的身份和机制的途径。将首先创建第一个血浆蛋白目录，该血浆蛋白直接越过BBB并量化其渗透率（目标1）。随后，我将通过推论信号来表征新的BBB继电器功能 BBB响应周围线索将大脑分泌到大脑中（AIM 2）。最后，我将阐明神经免疫通过确定BBB位点和分子的监视，使健康的免疫细胞迁移到大脑（目标3）。这些研究一起将扩大我们对BBB如何保持大脑健康和启用新的研究，探讨BBB可渗透蛋白和细胞在健康，衰老，，和疾病。我们的结果还将提供一组全面的功能目标，以增强药物输送到大脑，揭示了了解和钝神经炎症的新机制，并生成创新的工具破译细胞间通信，以跨学科的广泛使用。