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Microbial Dysbiosis and Epithelial Dysfunction in Vitamin A-deficient Lungs

维生素 A 缺乏肺中的微生物失调和上皮功能障碍

基本信息

批准号：
10607617
负责人：
Kiloni Quiles
金额：
$ 4.77万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
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：
2023-04-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10607617
关键词：
Adult Affect Asthma Biology Bronchoalveolar Lavage Fluid Cell Culture Techniques Cells Chronic Obstructive Pulmonary Disease Collection Communities Complex Core Facility Data Diet Disease Distal Ecosystem Environment Epithelium Event Exhibits Exposure to Functional disorder Future Gene Expression Genes Health Homeostasis Human Immune Impairment In Vitro Injections Knowledge Laboratories Link Lower respiratory tract structure Lung Lung diseases Lung infections Maintenance Malnutrition Mammals Measures Mediating Metabolic Metabolic Pathway Metabolism Microbe Microbial Biofilms Microscope Microscopy Modeling Mucociliary Clearance Mucous Membrane Mus Natural regeneration Outcome Paraffin Embedding Pathogenesis Pathology Pathway interactions Patients Pattern Peer Review Phenotype Physiological Processes Protocols documentation Publishing Pulmonary Pathology Quantitative Reverse Transcriptase PCR RNA Respiratory Disease Respiratory Tract Infections Risk Role SARS-CoV-2 infection Severities Sterility Structure of parenchyma of lung System Systems Biology Techniques Technology Testing Time Tissue Stains Tissues Trachea Tracheal Epithelium Transcript Tretinoin Tuberculosis Viral Vitamin A Vitamin A Deficiency Work airway epithelium airway immune response antimicrobial cell motility comparison control design dietary differential expression dysbiosis epithelial injury fluorescence imaging germ free condition gut dysbiosis gut microbiome host-microbe interactions immune function in silico in vivo interest lung health lung injury lung microbiome machine learning algorithm metatranscriptomics microbial microbial colonization microbial composition microbiome next generation sequencing novel permissiveness programs protein expression protein structure pulmonary function repaired

项目摘要

Abstract Once believed to be sterile, recent studies now show microbes inhabiting healthy lungs that are dysregulated in patients with chronic obstructive pulmonary disease (COPD), asthma, tuberculosis (TB), and SARS-CoV-2 infection. Malnourished patients have an increased risk of respiratory infections and pathogenesis according to recent studies, indicating a potential link between metabolic status and lung homeostasis. These and other studies indicate the presence of host-microbe-vitamin A interactions that are present in the lung and influence the respiratory immune response, however details of whether changes to the lung microbiome is a cause or consequence of lung pathology, or whether retinoic acid (RA) – the bioactive metabolite of Vitamin A – can directly influence the lung microbiome in a host-independent manner are largely unknown. We hypothesize that dietary VAD-induced airway epithelial remodeling promotes microbial dysbiosis in the lung, further perpetuating respiratory epithelial dysfunction via host-microbe interactions. Aim 1 will determine whether dietary VAD directly alters metabolic pathways of opportunistic microbes found upregulated in the lower respiratory tract (LRT) of adult VAD mouse lungs. Our Microscopy core facilities offer state-of-the-art microscopes designed to capture high-quality fluorescent images that will enable us to identify microbial composition, protein expression, and localization within the airway (1.1). Using qRT-PCR machines freely accessible to me in the Pulmonary Center, we will measure changes in relative abundance of the opportunistic microbes upregulated in VAS and VAD lungs at 3 weeks and 8 weeks post-dietary modulation (1.2). Aim 2 will determine whether locally-derived vs. distally-derived metabolic changes in the host could influence airway epithelial remodeling in the lower respiratory tract. We will measure ciliary motility in tracheal explants of VAS and VAD lungs using a ciliary motility protocol already completed by our laboratory (2.1). We will also investigate whether microbes have the ability to influence epithelial remodeling and ciliary function independent of host metabolic status. We aim to expose VAS and VAD tracheal explants to microbes from opposing diets in-vitro (2.2) and repeat the ciliary motility technique proposed in Aim 1. Our lab’s metatranscriptomic work paired with the Pulmonary department’s proven expertise in intratracheal viral injections and cell culture techniques makes this sub-aim easily achievable within the proposed time frame. Aim 3 will identify mechanisms associated with microbial metabolic functions that are dysregulated in the absence of vitamin A. We will measure RNA transcripts of our upregulated microbes via qRT-PCR gathered from our explanted tissues mentioned in Aim 2 (3.1). We will also investigate microbe-microbe and microbe-environment interactions using an in-silico community-based modeling program called COMETS (3.2), a platform created by our collaborators at the BU Microbiome Initiative. The results of this work aims to uncover specific host-microbe and microbe-microbe interactions in VAD lungs that are essential for healthy lung function.

摘要