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

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组成：呼吸道上皮具有湿润和湿润作用。另一方面，嗅觉上皮调节进入肺部的空气温度。专门用于化学感应并支持嗅觉感觉神经元检测空气中的气味剂（OSN）我们最近描述了嗅粘膜内的血管形成“血液嗅觉”。屏障”（BOB），防止高分子量血源蛋白进入嗅觉组织。这种 BOB 有效地将嗅觉组织与血源性分子隔离开来，其方式与在我们的研究中，我们发现血脑屏障和血视网膜屏障在大脑和眼睛中的功能。针对病毒病原体的抗体（~150kD）无法离开血液以防止嗅觉内的感染 BOB 的存在可能有助于调和多年来看似矛盾的上呼吸道。免疫数据，也有助于解释为什么 SARS-CoV-2 等病原体会感染嗅觉上皮当血液抗体滴度较高时，会导致“突破性感染”，我们对此基础知识知之甚少。该提案将建立这种新定义的血管屏障的细胞和分子构建模块。 BOB 稳态渗透性的限制以及有关 BOB 的一些基本见解，包括：从功能发育阶段到成年晚期，确定细胞和连接组成生成 BOB，定义健康和炎症期间的功能渗透性限制，最后确定嗅觉神经元在协调嗅觉屏障识别中的作用。