Mechanisms of regulatory T-cell mediated endothelial repair following viral pneumonia in aged hosts

老年宿主病毒性肺炎后调节性 T 细胞介导的内皮修复机制

基本信息

批准号：
10687164
负责人：
Luisa Morales-Nebreda
金额：
$ 16.12万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-20 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10687164
关键词：
2019-nCoV Acute Lung Injury Acute Respiratory Distress Syndrome Adoptive Transfer Affect Age Aging Alveolar Angiogenic Factor Antiviral Therapy Autopsy Biological Process Blood Vessels Blood capillaries Bronchoalveolar Lavage Fluid Case/Control Studies Cause of Death Cell Therapy Cells Clinical Data Dedications Development Diffuse Down-Regulation Elderly Endothelial Cells Endothelium Experimental Designs Failure Flow Cytometry Fluorescence-Activated Cell Sorting Functional disorder Gene Expression Profile Gene Expression Profiling Genetic Transcription Goals Human Immune Impairment Inflammation Influenza Influenza A virus Injury Knowledge Learning Link Longevity Lung Lymphocytic Infiltrate Measurement Mediating Mentors Methods Molecular Mus Older Population Organ Outcome Pathology Patients Phase Phenotype Physicians Pneumonia Population Predisposition Printing Production Proteins Publishing Pulmonary Inflammation Recovery Regulatory T-Lymphocyte Research Resolution Risk Factors Scientist Severities Specimen Techniques Testing Thrombosis Training Transgenic Organisms United States VEGFA gene Vascular Endothelial Growth Factors Viral Pneumonia Virus Virus Diseases Youth adaptive immune response age related aged alveolar epithelium angiogenesis career cell age design endothelial repair experience experimental study gain of function improved influenza infection influenzavirus insight loss of function lung injury lung repair mortality mouse model novel older patient overexpression programs recruit repair function repaired response to injury skills small molecule tissue repair transcriptome sequencing

项目摘要

PROJECT SUMMARY/ABSTRACT The broad objectives of this K08 proposal are two-fold: 1) to facilitate development of the necessary skills that will allow the candidate to achieve her long-term goal of becoming a successful physician-scientist focusing on determinants of recovery from viral pneumonia in aged hosts, and 2) to investigate the mechanisms that direct the Tregs to orchestrate resolution of severe lung injury throughout the lifespan. The candidate and her mentors have designed a detailed training plan tailored to the candidate's specific needs and goals. The plan includes a rigorous research component that will afford the PI new knowledge and research skills to better examine the links between a critical immune cell population and the endothelium during recovery from viral pneumonia. The proposal concerns viral pneumonia, specifically influenza-induced lung injury, its clinical counterpart the acute respiratory distress syndrome (ARDS) and how they both disproportionately affect the elderly population. Despite decades of dedicated research, there are only a few anti-viral therapies with limited efficacy to manage severe viral pneumonia. Tregs have been shown to decrease inflammation and promote tissue repair in diverse murine models of lung injury. Tregs also increase in the lungs of patients with ARDS, suggesting that they may play a role in the human adaptive immune response to lung injury. However, the specific mechanisms that cause Tregs to execute their pro-repair program following lung injury remain unknown. Our preliminary data shows that the youthful reparative Treg cell program following influenza-induced lung injury is dominated by biologic processes linked to the development and repair of blood capillaries. This reparative program is lost in aged hosts in a cell- autonomous manner. Thus, we hypothesize that aging results in Treg cell-specific downregulation of important pro-angiogenic factors expression such as VEGFA, leading to impaired alveolar endothelial repair and recovery from viral pneumonia. The long-term goal of the proposal is to identify novel small molecule- and cell-based therapeutics to control inflammation and promote tissue repair in our increasingly older population. To test this hypothesis, we propose the following Specific Aims: 1) determine whether age-related alterations in the pro- endothelial repair function of Tregs results from cell-autonomous or microenvironmentally-driven changes, 2) determine whether Treg cell-generated VEFGA is necessary and sufficient to restore the pro-endothelial repair function present in youth that is lost with aging, and 3) determine whether age-related VEGFA expression in alveolar Tregs in bronchoalveolar lavage fluid is associated with 30-day mortality in patients with severe viral pneumonia. We will use standard techniques to assess severity of lung injury, endothelial repair, heterochronic (age mis-matched) adoptive Treg cell transfer, multiple transgenic murine strains for loss-of-function and gain- of-function experiments, flow cytometry, fluorescence-activated cell sorting and transcriptional profiling with RNA-sequencing as the primary methods to support the experimental design of this proposal.

项目摘要/摘要该K08提案的广泛目标是两个方面：1）促进发展必要技能的发展将允许候选人实现她成为成功的医师科学家的长期目标从老年宿主中从病毒肺炎中恢复的决定因素，以及2）调查直接的机制在整个生命周期中，Tregs策划解决严重肺损伤的解决方案。候选人和她的导师已经设计了针对候选人的特定需求和目标量身定制的详细培训计划。该计划包括严格的研究组成部分，将负担PI的新知识和研究技能，以更好地检查从病毒性肺炎恢复期间，临界免疫细胞群体与内皮之间的联系。这提案涉及病毒性肺炎，特别是流感诱发的肺损伤，其临床对应于急性呼吸窘迫综合征（ARDS）以及它们如何对老年人群的影响不成比例。尽管数十年的专门研究，只有少数抗病毒疗法有限地管理严重的疗效病毒肺炎。 Treg已显示可减少炎症并促进多种鼠的组织修复肺损伤的模型。 Tregs还增加了ARDS患者的肺部，这表明他们可能会发挥人类对肺损伤的自适应免疫反应中的作用。但是，引起treg的特定机制在肺部受伤后执行其亲修改计划仍然未知。我们的初步数据表明流感诱导的肺损伤后，年轻的修复性Treg细胞计划由生物学过程主导与血液毛细血管的发展和修复有关。该修复程序在细胞中的老年宿主中丢失自主方式。因此，我们假设衰老会导致Treg细胞特异性下调促血管生成因子的表达，例如VEGFA，导致肺泡内皮修复和恢复受损来自病毒性肺炎。该提案的长期目标是确定新型的小分子和基于细胞的小分子在我们越来越老的人群中控制炎症并促进组织修复的治疗剂。测试这个假设，我们提出以下具体目的：1）确定促进年龄相关的变化是否存在 Tregs的内皮修复功能来自细胞自主或微环境驱动的变化，2）确定Treg细胞生成的VEFGA是否需要且足以恢复亲内皮修复年轻人丧失的年轻人的功能，3）确定与年龄相关的VEGFA表达是否在支气管肺泡灌洗液中的肺泡Tregs与严重病毒的患者的30天死亡率有关肺炎。我们将使用标准技术来评估肺损伤的严重程度，内皮修复，异位（年龄匹配的）收养Treg细胞转移，多个转基因鼠菌株用于功能丧失和增益功能实验，流式细胞术，荧光激活的细胞分选和转录分析 RNA序列是支持该提案实验设计的主要方法。