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

• 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
• 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

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.

项目摘要 免疫系统功能障碍与几种与年龄相关的肺部疾病的发病机制有关。 有趣的是，最近的多项研究已经确定，组织微环境在肿瘤的发生中起着关键作用。 这些年龄相关的免疫系统变化的发病机制。肺间质提供了一个 为居民免疫系统提供支持。因此，为了确定与年龄相关的肺部变化， 间充质可能有助于免疫系统功能障碍，我们进行了单细胞RNA测序 老年小鼠与年轻小鼠的肺间充质比较，确定核因子kappa-B（NF-kB）的证据 相对于年轻的外膜成纤维细胞，老年人中的活化。NF-kB是炎症的重要调节因子， 细胞衰老是一种多方面的细胞应激反应，其特征包括 永久的细胞周期停滞，细胞周期抑制剂16 INK 4a的表达，以及已知的复杂的分泌特征， 作为衰老相关的分泌表型。使用新型p16 INK 4a报告小鼠鉴定具有 我们发现p16 INK 4a+肺成纤维细胞富含NF-κ B活化， 随着年龄的增长在薄壁组织中积累。因此，为了研究间充质NF-kB活化在人骨髓瘤中的作用， 调节免疫系统，我们使用遗传模型有条件地删除Tnfaip 3，它编码一种 NF-kB信号传导的重要负调节因子，来自间充质。本提案中的初步数据 证明Tnfaip 3的间充质缺失导致CD 8 + T细胞在肺内的积累 年轻小鼠的外膜间充质，这些T细胞在转录上类似于衰老相关的 CD 8 + T细胞群（Taa）。因此，该提议的中心假设是NF-kB激活 在衰老成纤维细胞内的Taa在驱动肺Taa积累中起直接作用。目标1是确定 使用我们的新型p16 INK 4a+报告小鼠，肺成纤维细胞衰老对Taa形成的贡献。目的2 重点是确定间充质NF-kB驱动Taa形成的机制，Aim 3将 确定病毒性肺炎背景下Taa形成的功能后果。 本提案的培训计划旨在实现艾伦博士的目标， 研究肺间质和免疫系统之间相互作用的独立医生-科学家 健康和疾病。该计划包括正式的教学法，会议，指导和实践经验 尽管如此，艾伦博士将在细胞衰老、适应性免疫、 肺部感染，肺间充质和相关的上皮干细胞尼斯，以及负责， 有效的研究实践。她将得到一个强大的导师团队的支持， 生物学、细胞衰老、组织驻留淋巴细胞和NF-kB信号传导。随着这一职业生涯的结束， 发展奖艾伦博士将对肺免疫的理解做出宝贵贡献 系统老化，并将充分准备推出她的独立职业生涯。