Molecular tools to decipher communication across the blood-brain barrier

破译跨血脑屏障通讯的分子工具

• 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
• 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

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.

项目总结/摘要 血脑屏障（BBB）通过保护大脑免受血流影响来维持大脑健康。这些 屏障特性阻碍了几乎所有脑部疾病的治疗，代表了最大的 神经科学和药物输送的挑战。然而，有趣的是，最近的研究发现， 令人惊讶的是，大脑功能的外围影响，暗示存在未被重视的模式， 通过BBB进行通信。事实上，虽然典型的BBB特性，如细胞旁紧密连接， 和最低限度的小窝蛋白介导的转胞吞作用，已经通过一些标准示踪剂建立，它 目前尚不清楚这些示踪剂是否完全代表了血脑屏障的生理相互作用， 它对成千上万的循环蛋白质和细胞的渗透性是不断暴露的。发展中 方法标记和跟踪血浆蛋白质组，我最近观察到一个意想不到的程度和多样性 蛋白质运输到健康成年人的大脑中。因此，我假设大脑健康的维持不仅仅是 血脑屏障的不渗透性-但通过血脑屏障积极促进的特定的血脑通讯途径。 具体地说，我认为有三种逻辑路径可以用来描述外围信息的交流方式 通过健康的血脑屏障：蛋白质直接运输到大脑;蛋白质的响应中继， BBB进入脑;以及BBB许可的外周免疫细胞迁移进入脑。通过组合 蛋白质组标记技术与生物正交化学，每个提出的目标探索一个独立的 这是一种系统地揭示通过健康BBB传输的信号的身份和机制的途径。我 将开始通过创建直接穿过血脑屏障的血浆蛋白的第一个目录，并定量它们的 渗透率（目标1）。随后，我将通过推导信号来描述新的BBB中继功能 BBB响应于外周线索而分泌到大脑中（目的2）。最后，我将阐明神经免疫 通过确定能够使健康免疫细胞迁移到大脑中的BBB位点和分子进行监测 (Aim 3）。总之，这些研究将扩大我们对BBB如何维持大脑健康的理解， 使新的研究能够探索BBB渗透蛋白和细胞在健康，衰老， 和疾病我们的研究结果还将提供一套全面的功能靶点，以增强药物递送， 大脑，揭示了理解和钝化神经炎症的新机制，并产生了创新的工具 来破译细胞间的通讯，以供跨学科的广泛使用。