Defining the molecular and anatomical basis of the blood-olfactory barrier (BOB)

定义血嗅屏障（BOB）的分子和解剖学基础

基本信息

批准号：
10723087
负责人：
E. Ashley Moseman
金额：
$ 43.39万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10723087
关键词：
2019-nCoV Ablation Adult Age Aging Air Anatomy Animals Anosmia Antibodies Antibody titer measurement Astrocytes Binding Biology Blood Blood - brain barrier anatomy Blood Proteins Blood Vessels Blood-Retinal Barrier Brain Cells Central Nervous System Central Nervous System Agents Clinical Treatment Complex Data Detection Development Disease Drug Delivery Systems Electron Microscopy Endothelial Cells Endothelium Epithelium Esthesia Exclusion Eye Genetic Transcription Goals Health Health system Host Defense Immune Immunity Infection prevention Inflammation Inflammation Mediators Inflammatory Invaded Knowledge Lung Lung diseases Maintenance Microscopy Molecular Molecular Weight Movement Nasal turbinate bone structure Neurons Nose Olfactory Epithelium Olfactory Mucosa Organ Pericytes Permeability Plasma Proteins Proteins Publishing Regulation Role Temperature Tight Junctions Tissues Toxin Upper respiratory tract Vaccine Design Vascular Endothelial Cell Work airway epithelium breakthrough infection cell growth regulation empowerment expectation genetic approach insight microbial novel olfactory sensory neurons pathogen pathogenic virus perineural prevent respiratory solute transcriptomics vaccinology

2019-nCoV Ablation Adult Age Aging Air Anatomy Animals Anosmia Antibodies Antibody titer measurement Astrocytes Binding Biology Blood Blood - brain barrier anatomy Blood Proteins Blood Vessels Blood-Retinal Barrier Brain Cells Central Nervous System Central Nervous System Agents Clinical Treatment Complex Data Detection Development Disease Drug Delivery Systems Electron Microscopy Endothelial Cells Endothelium Epithelium Esthesia Exclusion Eye Genetic Transcription Goals Health Health system Host Defense Immune Immunity Infection prevention Inflammation Inflammation Mediators Inflammatory Invaded Knowledge Lung Lung diseases Maintenance Microscopy Molecular Molecular Weight Movement Nasal turbinate bone structure Neurons Nose Olfactory Epithelium Olfactory Mucosa Organ Pericytes Permeability Plasma Proteins Proteins Publishing Regulation Role Temperature Tight Junctions Tissues Toxin Upper respiratory tract Vaccine Design Vascular Endothelial Cell Work airway epithelium breakthrough infection cell growth regulation empowerment expectation genetic approach insight microbial novel olfactory sensory neurons pathogen pathogenic virus perineural prevent respiratory solute transcriptomics vaccinology

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项目摘要

The upper respiratory tract is lined by two distinct types of epithelium. Respiratory epithelium humidifies and modulates incoming air temperature as it passes toward the lungs. Olfactory epithelium on the other hand is specialized for chemosensation and supports detection of airborne odorants by olfactory sensory neurons (OSNs). We have recently described that blood vessels within the olfactory mucosa form a “blood -olfactory barrier” (BOB) that prevents high molecular weight blood borne proteins from accessing the olfactory tissues. This BOB effectively isolates olfactory tissues from blood borne molecules in much the same way that the blood brain barrier and the blood retinal barrier function in the brain and eye. In our studies we found that antibodies (~150kD) against viral pathogens cannot exit the blood to prevent infections within the olfactory epithelium. The existence of the BOB may help reconcile years of seemingly contradictory upper airway immunity data, and also helps explain why pathogens such as SARS-CoV-2 that infect the olfactory epithelium cause “breakthrough infections” when blood antibody titers are high. We know very little about the basic cellular and molecular building blocks of this newly defined vascular barrier. This proposal will establish the limits of BOB homeostatic permeability and several foundational insights about the BOB, including: BOB functionality from developmental stages until late adulthood, determine the cellular and junctional makeup that generates the BOB, define the functional permeability limits during health and inflammation, and finally determine the role of olfactory neurons in orchestrating olfactory barrier identity.

上呼吸道由两种不同类型的上皮衬里。呼吸性上皮潮湿调节传入的气温向肺部传递时。另一方面，嗅觉上皮是专门用于化学一度并支持嗅觉神经元检测空气传播的气味剂（OSN）。我们最近描述的是，嗅觉粘膜内的血管形成“血液 - 野血屏障”（BOB）可防止高分子体重血液生产蛋白进入嗅觉组织。这种鲍勃有效地将嗅觉组织与血液传播分子分离，与血脑屏障和血液残留屏障在大脑和眼睛中的功能。在我们的研究中，我们发现针对病毒病原体的抗体（〜150KD）不能退出血液以防止嗅觉内感染上皮。鲍勃的存在可能有助于调和几年看似矛盾的上呼吸道免疫数据，还有助于解释为什么感染嗅觉上皮的病原体（例如SARS-COV-2）当血抗体滴度高时，引起“突破感染”。我们对基本知之甚少这个新定义的血管屏障的细胞和分子构建块。该建议将确定鲍勃稳态渗透性的极限和关于鲍勃的几个基本见解，包括：鲍勃从发展阶段到成年后期的功能性，确定细胞和交界的化妆生成BOB，定义健康和感染期间的功能渗透率限制，最后确定嗅觉神经元在修复嗅觉屏障身份中的作用。