Molecular Mechanisms of the Blood Brain Barrier Function and Regulation

血脑屏障功能与调节的分子机制

• 批准号: 10611869
• 负责人: CHENGHUA GU
• 金额: $ 100.93万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10611869
• 关键词: Alzheimer' s Disease; Astrocytes; Biochemical; Biological Models; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain Neoplasms; Candidate Disease Gene; Cell Line; Cells; Cellular biology; Central Nervous System; Central Nervous System Diseases; Cerebrovascular system; Chemicals; Controlled Environment; Disease; Drug Delivery Systems; Endocytic Vesicle; Endothelial Cells; Endothelium; Ensure; Environment; Goals; Image; Imaging Device; Mental disorders; Molecular; Multiple Sclerosis; Nerve Degeneration; Neurodegenerative Disorders; Neurologic; Neurology; Parkinson Disease; Pathologic; Pathway interactions; Pericytes; Physiological; Positioning Attribute; Regulation; Signal Transduction; Stroke; Synaptic Transmission; Therapeutic; Therapeutic Agents; Tight Junctions; Toxin; Translating; Work; blood-brain barrier crossing; blood-brain barrier function; blood-brain barrier permeabilization; brain endothelial cell; experimental study; mouse genetics; nervous system disorder; neuroinflammation; novel therapeutics; pathogen; public health relevance; seal; tool; transcriptome; transcytosis; vesicle transport

Project Summary/Abstract: The central nervous system (CNS) requires a tightly controlled environment free of various toxins and pathogens to provide the proper chemical composition for synaptic transmission. This environment is maintained by the `blood brain barrier' (BBB), which is composed of highly specialized blood vessels whose endothelial cells display specialized tight junctions and unusually low rates of transcellular vesicular transport (transcytosis). In concert with pericytes and astrocytes, this unique brain endothelial physiological barrier seals the CNS and controls substance influx and efflux. While BBB breakdown has recently been associated to initiation and perpetuation of various neurological disorders, an intact BBB is a major obstacle for drug delivery to the CNS. A limited understanding of the molecular mechanisms that control BBB formation has hampered our ability to manipulate the BBB in disease. Our recent discoveries changed our understanding of what makes the BBB impermeable. The BBB is formed by a single layer of endothelial cells that lines the walls of the brain's blood vessels. Historically, the restrictive feature of BBB has been attributed to the specialized tight junctions between adjacent endothelial cells. However, substances can also cross the endothelial layer by transcytosis, when material enters endocytic vesicles that are trafficked across the cell. We discovered that transcytosis is actively inhibited in brain endothelial cells to ensure BBB integrity. Our findings suggest that molecular pathways inhibiting transcytosis could be targeted to open the BBB for CNS therapeutics.We have also identified over 200 BBB candidate genes that are enriched in CNS endothelial cells compared to periphery endothelial cells. I propose to launch major new efforts leading to a major expansion in the scope of our work in the field of BBB. I will take the next eight years to bring my lab to the next level to (1) identify the full list of key BBB regulators in CNS endothelial cells, (2) understand what signals from non-endothelial cells maintain and regulate BBB permeability, and (3) determine how BBB permeability dynamically changes during different physiological and pathological conditions. We will also begin to work on translating findings from these studies to therapies. We will use a combination of mouse genetics, imaging, molecular, cell biology, and biochemical approaches. The experiments described here represent a major expansion in the scope of our work. Achieving the goals outlined here could have a major impact on neurology, enabling clinicians to open the BBB for transient delivery of drugs to the CNS, and conversely to close the BBB to slow the progression of neurodegenerative diseases. Given the transcriptome screens we have recently performed, the model systems we have devised, and the imaging tools we have recently developed, my lab is in a unique position to reveal the molecular and cellular mechanisms of the BBB.

项目摘要/摘要： 中枢神经系统(CNS)需要一个严格受控的环境，没有各种毒素和 病原体为突触传递提供适当的化学成分。这个环境是 由血脑屏障(BBB)维持，该屏障由高度专业化的血管组成，其 内皮细胞表现出特殊的紧密连接和异常低的跨细胞囊泡转运率。 (跨细胞反应)。与周细胞和星形胶质细胞协同作用，这种独特的脑内皮生理屏障密封 中枢神经系统和控制物质的流入和流出。虽然血脑屏障故障最近被认为与 各种神经系统疾病的开始和延续，完整的血脑屏障是药物输送的主要障碍。 送到中枢神经系统。对控制血脑屏障形成的分子机制的有限了解阻碍了 我们在疾病中操纵血脑屏障的能力。我们最近的发现改变了我们对 使血脑屏障不透水。血脑屏障是由一层内皮细胞组成的，它排列在血管壁上 大脑的血管。从历史上看，血脑屏障的限制性特征被归因于专门化的紧缩性 相邻内皮细胞之间的连接。然而，物质也可以通过以下方式穿过内皮层 跨细胞作用，当物质进入跨细胞运输的内吞囊泡时。我们发现 在脑内皮细胞中，跨细胞作用被主动抑制，以确保血脑屏障的完整性。我们的发现表明 抑制细胞转运的分子途径可以靶向打开中枢神经系统治疗的血脑屏障。 还鉴定了200多个BBB候选基因，与外周相比，这些基因在中枢神经系统内皮细胞中丰富 内皮细胞。我建议开展新的重大努力，使我们的工作范围得到重大扩大 在BBB领域。我将在接下来的八年里将我的实验室提升到一个新的水平：(1)确定完整的清单 中枢神经系统内皮细胞中关键的血脑屏障调节因子，(2)了解来自非内皮细胞的信号维持 并调节血脑屏障通透性，以及(3)确定血脑屏障通透性在不同时期的动态变化 生理和病理条件。我们还将开始将这些研究的结果转化为 为治疗干杯。我们将使用小鼠遗传学、成像学、分子生物学、细胞生物学和生化的组合 接近了。这里描述的实验代表着我们工作范围的重大扩展。实现 这里概述的目标可能会对神经学产生重大影响，使临床医生能够打开BBB 短暂地将药物输送到中枢神经系统，反过来关闭血脑屏障，以减缓疾病的进展 神经退行性疾病。考虑到我们最近进行的转录屏幕，模型系统 我们设计的，以及我们最近开发的成像工具，我的实验室处于一个独特的位置来揭示 血脑屏障的分子和细胞机制。