Olfactory mucosa repair and defense: neuro-immune mechanisms and therapy

嗅粘膜修复和防御：神经免疫机制和治疗

• 批准号: 10576543
• 负责人: ANDREW P LANE
• 金额: $ 67.02万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10576543
• 关键词: 2019-nCoV; Address; Affect; Anatomy; Anosmia; Apical; Basal Cell; Bipolar Neuron; Brain; COVID-19 pandemic; Cell Communication; Cell Differentiation process; Cell Line; Cell Proliferation; Cell physiology; Cells; Chemicals; Chronic; Communication; Environment; Epithelium; Foundations; Genes; Goals; Health; Human; Immune; Immune response; Immune signaling; Immune system; Impairment; In Vitro; Individual; Infection; Inflammation; Inflammatory; Inhalation; Injury; Innate Immune Response; Innovative Therapy; Irritants; Knowledge; Location; Maintenance; Mediating; Mesenchymal; Microbe; Modeling; Mucociliary Clearance; Mucous Membrane; Mus; Nasal Polyps; Natural regeneration; Nerve Regeneration; Neuroepithelial; Neuroimmune; Neuroimmunomodulation; Neurons; Nose; Olfactory Epithelial Cell; Olfactory Epithelium; Olfactory Mucosa; Olfactory Pathways; Organ; Pathway interactions; Pattern recognition receptor; Phagocytes; Physiological; Play; Process; Pseudostratified Epithelium; Quality of life; Receptor Signaling; Research; Respiratory Mucosa; Rest; Role; SARS-CoV-2 infection; Sampling; Sensory; Shapes; Signal Pathway; Signal Transduction; Site; Smell Perception; Stimulus; Structure; Surface; Testing; Tissues; Transcriptional Regulation; United States; Virus; Virus Diseases; Work; airway epithelium; cell type; chemokine; cilium motility; cytokine; differential expression; epithelial injury; experimental study; fighting; immune cell infiltrate; immune function; immunoregulation; in vivo; insight; mouse model; neuroepithelium; neuropeptide Y; notch protein; novel; pathogen; progenitor; reconstitution; repaired; response; scaffold; self-renewal; single-cell RNA sequencing; stem cells; stemness; sustentacular cell; trafficking; transcription factor; transcriptome sequencing; transcriptomics

Project summary: The olfactory epithelium is situated in the nasal passages at the interface with the environment – a location that makes it vulnerable to damage by both infectious and non-microbial threats. While the innate immune defenses of the respiratory epithelium are increasingly well understood, the immune mechanisms protecting the delicate olfactory neuroepithelium have not been fully elucidated. Inflammation of the olfactory epithelium can result in the loss of the sense of smell, which is a debilitating health problem in the United States significantly impacting the quality of life of affected individuals. The current COVID-19 pandemic has highlighted how viral infection and the local immune response of the olfactory epithelium can impair sense of smell function, although the mechanism is unknown. We hypothesize that the lining cells of the olfactory epithelium, called sustentacular cells, play a critical role protecting the underlying neurons by maintaining a strong physical barrier and providing a supporting framework. Once damaged, olfactory tissue has a remarkable and unique neuroregenerative capacity, allowing rapid repair by creation of new neurons. The signals that drive and regulate regeneration by olfactory progenitor cells are unclear. Our preliminary studies in mice reveal that regulated inflammation is important to initiating normal repair after olfactory injury. We also have found that olfactory stem cells deep in the mucosa are capable of communicating with immune cells to mediate inflammation. In this way, we propose that olfactory stem cells provide innate immune protection to the epithelium. We hypothesize that injury to the surface barrier exposes olfactory stem cells to stimuli that drive inflammation and replacement of apical cells. The overall goal of this proposal is to explore neuroepithelial-immune interactions in the olfactory epithelium. In aim 1, we will investigate the innate immune activity of olfactory stem cells and demonstrate whether inflammatory cells and their chemical signals modulate basal cell function. In aim 2, we will explore the role of stem cells in modulating the immune response and in fighting infection. Finally, in aim 3, we will study the immune response of sustentacular cells and olfactory stem cells to inflammatory signals related to two common causes of loss of the sense of smell: nasal polyps and infection with SARS-CoV-2. These studies will significantly advance current knowledge about the olfactory system and create an opportunity to develop innovative therapies for important health conditions impacting the sense of smell.

项目概要： 嗅上皮位于鼻通道中与环境的界面处 - 一个位置，使它容易受到损害的传染性和非微生物的威胁。 虽然呼吸道上皮的先天免疫防御能力越来越好， 据了解，保护脆弱嗅觉神经上皮的免疫机制尚未 被充分阐明。嗅上皮炎症可导致感觉丧失 气味，这是一个削弱健康问题，在美国显着影响 受影响个人的生活质量。当前的COVID-19大流行凸显了病毒如何 感染和嗅上皮的局部免疫反应可损害嗅觉 功能，虽然机制不明。我们假设， 嗅上皮，称为支持细胞，起着关键作用，保护底层 通过维持强大的物理屏障并提供支持框架来保护神经元。一旦 受损的嗅觉组织具有非凡而独特的神经再生能力， 通过产生新的神经元进行快速修复。驱动和调节再生的信号， 嗅觉祖细胞尚不清楚。我们对小鼠的初步研究表明， 炎症对于嗅觉损伤后启动正常修复是重要的。我们还发现 粘膜深处的嗅觉干细胞能够与免疫细胞沟通， 介导炎症。通过这种方式，我们提出嗅觉干细胞提供先天免疫， 保护上皮细胞。我们假设表面屏障的损伤暴露了嗅觉 干细胞刺激，驱动炎症和顶细胞的替代。的总目标 本研究旨在探讨嗅上皮中神经上皮-免疫的相互作用。在 目的1，我们将研究嗅觉干细胞的天然免疫活性，并证明 炎症细胞及其化学信号是否调节基底细胞功能。在目标2中，我们 将探讨干细胞在调节免疫反应和对抗感染中的作用。 最后，在aim 3中，我们将研究支持细胞和嗅干的免疫反应 细胞的炎症信号有关的两个共同的原因丧失嗅觉：鼻 息肉和感染SARS-CoV-2。这些研究将大大推动当前 了解嗅觉系统，并创造机会开发创新疗法 影响嗅觉的重要健康状况。