Complement Pathway Activation in Idiopathic Pulmonary Fibrosis and other Progressive Fibrosing Interstitial Lung Diseases

特发性肺纤维化和其他进行性纤维化间质性肺疾病中的补体途径激活

• 批准号: 10590870
• 负责人: Aparna Chandra Swaminathan
• 金额: $ 18.93万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10590870
• 关键词: Acceleration; Acute; Admission activity; Animal Model; Area; Biological; Biological Markers; Biology; Biometry; Case/Control Studies; Cessation of life; Chronic; Classification; Clinical Data; Clinical Research; Clinical Trials; Code; Complement; Complement 3b; Complement 4b; Complement 5a; Complement Activation; Complement component C1r; Cox Proportional Hazards Models; DNA; Data; Data Set; Deterioration; Development; Disease Progression; Dyspnea; Enrollment; Epithelial Cells; Etiology; Event; Fibroblasts; Fibrosis; Funding; Future; Generations; Genes; Genetic; Genetic Polymorphism; Genetic Risk; Genetic Variation; Goals; Hospitalization; Host Defense; Immunology; Inflammation; Institution; Intervention; Knowledge; Laboratories; Lead; Linear Regressions; Logistic Regressions; Lung; Lung Transplantation; Lung diseases; Measures; Mentored Patient-Oriented Research Career Development Award; Mentors; Mentorship; Messenger RNA; Modeling; Outcome; Pathway interactions; Patient-Focused Outcomes; Patients; Phenotype; Plasma; Positioning Attribute; Prospective cohort; Proteins; Pulmonary Fibrosis; Registries; Regression Analysis; Research; Research Institute; Research Personnel; Research Training; Respiratory Failure; Risk; Role; Sampling; Structure of parenchyma of lung; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Training; Transcript; Translational Research; Variant; Vital capacity; biobank; career development; case control; clinically relevant; cohort; complement pathway; disorder risk; effective therapy; exome sequencing; experience; externship; fibrotic interstitial lung disease; fibrotic lung; follow-up; genetic risk factor; genetic variant; genome sequencing; hands on research; idiopathic pulmonary fibrosis; improved outcome; insight; lung development; mortality; multidisciplinary; novel; personalized medicine; potential biomarker; prevent; prognostic; prospective; pulmonary function decline; receptor expression; recruit; research and development; respiratory; symposium; targeted treatment; therapeutically effective; whole genome

Project Summary/Abstract Idiopathic pulmonary fibrosis (IPF) and other progressive fibrosing interstitial lung diseases (PF-ILDs) lead to inexorable lung function decline and death despite available treatments. Patients with PF-ILD can also experience acute respiratory deteriorations known as acute exacerbations (AE), which carry a high short-term mortality, lack approved treatments, and are poorly understood. Dr. Swaminathan’s long-term goal is to develop novel treatments for PF-ILD that improve outcomes and to use biomarkers to personalize therapies in PF-ILD. The overall objective of this application is to investigate the role of the complement pathway as a biomarker in PF-ILD disease progression, AE, and as a genetic risk factor for PF-ILD development and progression. The central hypothesis is that complement activation, as reflected either by C3b, C4b, or C5a protein generation or genetic variation, associates with PF-ILD progression, AE events, and AE outcomes. The rationale for this project is that identification of complement activation as a biomarker in PF-ILD progression or AE will identify patients for whom further intervention with complement-related therapies is warranted, expanding treatment options for patients with PF-ILD. The central hypothesis will be tested by pursuing three specific aims. In Aim 1, plasma C3b, C4b, and C5a will be quantified in 1,273 PF-ILD patients at baseline and 6 months of follow up to determine the association with a composite measure of disease progression. Aim 2 will recruit a prospective cohort of PF- ILD patients with AE (n=50) to determine the association of plasma C3b, C4b, and C5a with 90-day death or lung transplant and to compare C3b, C4b, and C5a in the plasma and lung tissue of patients with versus without AE. Aim 3 will leverage existing whole genome sequencing in patients with IPF (n=912) and newly generated whole exome sequencing in patients with non-IPF PF-ILD (n=400) to identify protein-coding variants in complement-related genes that confer risk for PF-ILD and associate with PF-ILD progression or AE. By completing the scientific aims and the career development activities of this proposal, Dr. Swaminathan will acquire rigorous clinical and translational research training, including in-depth knowledge of complement biology. Her career development activities will also build new expertise in these areas through graduate-level didactics in immunology and biostatistics, complement-focused conferences, laboratory externships, experiential training in clinical trials at the Duke Clinical Research Institute, and carefully mentored hands-on research experiences. Dr. Swaminathan’s research and career development will be guided by a multidisciplinary mentorship team with expertise in IPF, complement biology, translational pulmonary research, and biostatistics. Her scientific advisors will add further depth in complement activation, genetics, and pulmonary fibrosis mechanisms. The research training, along with strong institutional support, will accelerate Dr. Swaminathan’s transition to an independently- funded investigator to conduct trials evaluating complement-related therapies in patients with PF-ILD targeted in a personalized manner.

项目总结/摘要 特发性肺纤维化（IPF）和其他进行性纤维化间质性肺病（PF-ILD）导致 无法避免的肺功能下降和死亡。PF-ILD患者还可以 经历称为急性加重（AE）的急性呼吸恶化，其携带高的短期 死亡率，缺乏批准的治疗方法，并且知之甚少。斯瓦米纳坦博士的长期目标是 PF-ILD的新型治疗方法，可改善结局，并使用生物标志物对PF-ILD进行个性化治疗。 本申请的总体目标是研究补体途径作为生物标志物在免疫缺陷病毒中的作用。 PF-ILD疾病进展、AE，以及作为PF-ILD发生和进展的遗传风险因素。的 中心假设是补体激活，如通过C3 b、C4 b或C5 a蛋白产生或 遗传变异与PF-ILD进展、AE事件和AE结局相关。该项目的基本原理 将补体激活鉴定为PF-ILD进展或AE中生物标志物是否将识别患者 对于需要进一步进行补体相关治疗的患者， PF-ILD患者。中心假设将通过追求三个具体目标来检验。在目标1中，血浆 将在基线和6个月随访时对1，273例PF-ILD患者的C3 b、C4 b和C5 a进行定量，以确定 与疾病进展的复合指标的相关性。目标2将招募一个前瞻性的PF队列- 发生AE的ILD患者（n=50），以确定血浆C3 b、C4 b和C5 a与90天死亡或 肺移植，并比较C3 b，C4 b和C5 a在血浆和肺组织的患者与没有 AE.目标3将利用IPF患者（n=912）和新生成的 在非IPF PF-ILD患者（n=400）中进行全外显子组测序，以鉴定 赋予PF-ILD风险并与PF-ILD进展或AE相关的补体相关基因。通过 完成本提案的科学目标和职业发展活动，Swaminathan博士将 获得严格的临床和转化研究培训，包括补体生物学的深入知识。 她的职业发展活动也将通过研究生水平的教学法在这些领域建立新的专业知识 在免疫学和生物统计学，补体为重点的会议，实验室实习，经验培训 在杜克临床研究所进行临床试验，并仔细指导实践研究经验。 博士斯瓦米纳坦的研究和职业发展将由一个多学科的导师团队指导， 在IPF、补体生物学、转化肺研究和生物统计学方面的专业知识。她的科学顾问 将进一步深入研究补体激活、遗传学和肺纤维化机制。研究 培训，沿着强有力的机构支持，将加速斯瓦米纳坦博士向独立工作的过渡， 受资助的研究者开展试验，评价针对以下疾病的PF-ILD患者的补体相关治疗： 个性化的方式。