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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：
10491354
负责人：
Luisa Morales-Nebreda
金额：
$ 16.17万
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/10491354
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 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 Infiltration Inflammation Influenza Influenza A virus Injury Knowledge Learning Link Longevity Lung Lymphocyte Measurement Mediating Mentors Methods Molecular Target Mus Older Population Outcome Pathology Patients Phase Phenotype Physicians Play Pneumonia Population Predisposition Proteins Publishing Pulmonary Inflammation Recovery Regulatory T-Lymphocyte Research Resolution Risk Factors Role Scientist Severities Specimen Techniques Testing Thrombosis Training Transgenic Organisms United States VEGFA gene Viral 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.

项目总结/文摘