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Role of stromal inflammatory signaling in the aging of lung resident lymphocytes

基质炎症信号在肺驻留淋巴细胞衰老中的作用

基本信息

批准号：
10723431
负责人：
Nancy Christine Allen
金额：
$ 16.9万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
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：
2023-08-15 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10723431
关键词：
Address Age Age Factors Aging Alveolus Antibodies Automobile Driving Basal Cell Biological Assay Biology CD8-Positive T-Lymphocytes CD8B1 gene CDKN2A gene Cell Aging Cell Communication Cell Cycle Cell Cycle Arrest Cells Cellular Stress Chronic Obstructive Pulmonary Disease Circulation Coculture Techniques Complex Dasatinib Data Development Disease Elderly Exhibits Fibroblasts Fibrosis Gene Expression Profile Genetic Models Genetic Transcription Goals Health Histology Homeostasis Hydroxyproline I Kappa B-Alpha Immune Immune System Diseases Immune system Immunohistochemistry Impairment In Vitro Infection Inflammation Inflammatory Influenza K-Series Research Career Programs Kinetics Lung Lung diseases Lung infections Lymphocyte Lymphoid Mentorship Mesenchymal Mesenchyme Morbidity - disease rate Mus Names Nuclear Pathogenesis Pathologic Phenotype Physicians Play Pneumonia Population Production Pulmonary Fibrosis Quercetin Reporter Research Role Scientist Signal Induction Signal Transduction Source T-Lymphocyte Testing Tissues Training Transplantation Uncertainty Up-Regulation Viral Viral Load result Viral Pneumonia Virus Diseases adaptive immunity age related aged anti-PD-1 career chemokine cytokine differential expression emerging adult epithelial stem cell exhaustion experience improved in vitro testing in vivo in vivo evaluation inhibitor knock-down lung health lung repair mortality mouse model neutralizing antibody novel programmed cell death protein 1 recruit senescence single-cell RNA sequencing symposium therapeutic target therapy development tissue injury tissue repair transcriptome sequencing

项目摘要

PROJECT SUMMARY Immune system dysfunction has been implicated in the pathogenesis of several age-related lung diseases. Interestingly, multiple recent studies have identified the tissue microenvironment as playing a critical role in the pathogenesis of some of these age-related immune system changes. The lung mesenchyme provides a supportive niche for the resident immune system. Therefore, to identify aging-related changes in the lung mesenchyme that might contribute to immune system dysfunction, we performed single-cell RNA-sequencing of lung mesenchyme from aged versus young mice, identifying evidence of nuclear-factor kappa-B (NF-kB) activation in aged relative to young adventitial fibroblasts. NF-kB is an important regulator of inflammation and cellular senescence, a multifaceted cellular stress response characterized by several features including permanent cell cycle arrest, expression of the cell cycle inhibitor 16INK4a, and a complex secretory profile known as the senescence-associated secretory phenotype. Using a novel p16INK4a reporter mouse to identify cells with senescent features in vivo, we found that p16INK4a+ lung fibroblasts were enriched for NF-kB activation and accumulated in the parenchyma with age. Therefore, to study the effects of mesenchymal NF-kB activation in regulating the immune system, we used a genetic model to conditionally delete Tnfaip3, which encodes an important negative regulator of NF-kB signaling, from the mesenchyme. Preliminary data in this proposal demonstrates that mesenchymal deletion of Tnfaip3 leads to the accumulation of CD8+ T cells within the lung adventitial mesenchyme of young mice, and that these T cells transcriptionally resemble an aging-associated CD8+ T cell population (Taa). Therefore, the central hypothesis of this proposal is that NF-kB activation within senescent fibroblasts plays a direct role in driving lung Taa accumulation. Aim 1 is to identify the contribution of lung fibroblast senescence to Taa formation using our novel p16INK4a+ reporter mouse. Aim 2 focuses on identifying the mechanism by which mesenchymal NF-kB drives Taa formation, and Aim 3 will determine the functional consequences of Taa formation in the setting of viral pneumonia. The training plan for this proposal has been developed to achieve Dr. Allen’s goal of becoming an independent physician-scientist studying the interactions between the lung mesenchyme and immune system in health and disease. The plan involves formal didactics, conferences, mentorship, and hands-on experience though which Dr. Allen will develop expertise in cellular senescence, adaptive immunity, mouse models of pulmonary infection, the lung mesenchyme and associated epithelial stem cell nice, as well as responsible and effective research practices. She will be supported by a strong mentorship team with expertise spanning lung biology, cellular senescence, tissue resident lymphocytes, and NF-kB signaling. With completion of this Career Development Award Dr. Allen will have made valuable contributions to the understanding of lung immune system aging, and will be well-prepared to launch her independent career.

项目总结