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.

项目概要/摘要 血脑屏障（BBB）通过保护大脑免受血液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，这是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，最近的研究发现了多种 令人惊讶的外周对大脑功能的影响，暗示存在未被充分认识的模式 通过 BBB 进行通信。事实上，虽然典型的血脑屏障特性，例如细胞旁紧密连接 和最小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起来，它 目前尚不清楚这些示踪剂是否完全代表 BBB 与 和 的生理相互作用 对其不断接触的数千种循环蛋白质和细胞的渗透性。通过开发 标记和追踪血浆蛋白质组的方法，我最近观察到意想不到的程度和多样性 蛋白质运输到健康成人大脑的过程。因此，我假设大脑健康的维持不仅仅是通过 血脑屏障不可渗透性——但通过血脑屏障积极促进的血液与大脑的特定通讯途径。 具体来说，我建议外围信息的通信方式有三种逻辑路线 穿过健康的血脑屏障：将蛋白质直接输送到大脑；蛋白质的反应中继 BBB进入大脑；以及 BBB 许可的外周免疫细胞向大脑的迁移。通过结合 蛋白质组标记技术与生物正交化学，每个提出的目标都探索一个独立的目标 系统地揭示通过健康 BBB 传输的信号的身份和机制。我 首先将创建第一个直接穿过血脑屏障的血浆蛋白目录并量化它们 渗透率（目标 1）。随后我将通过推导信号来描述新的 BBB 继电器功能 BBB 会根据外周信号分泌到大脑中（目标 2）。最后我来解释一下神经免疫 通过确定 BBB 位点和分子来实现健康免疫细胞迁移到大脑中的监测 （目标 3）。总之，这些研究将扩大我们对 BBB 如何维持大脑健康和 促进新的研究探索血脑屏障渗透性蛋白质和细胞在健康、衰老、 和疾病。我们的结果还将提供一套全面的功能目标，以增强药物输送 大脑，揭示理解和减轻神经炎症的新机制，并产生创新工具 破译细胞间通讯以供跨学科广泛使用。