Personalized Model Systems to Predict and Investigate CFTR Drug Response in CF

用于预测和研究 CF 中 CFTR 药物反应的个性化模型系统

• 批准号: 10223422
• 负责人: John Joseph Brewington
• 金额: $ 16.36万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10223422
• 关键词: Alleles; Automobile Driving; Biochemical; Biological Assay; Biological Models; Biology; Caring; Caucasians; Cell membrane; Cell model; Cells; Center for Translational Science Activities; Childhood; Chlorides; Clinical; Clinical Data; Conduct Clinical Trials; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Data; Defect; Delta F508 mutation; Development; Disease; Drug Prescriptions; Drug Targeting; Epithelial; Epithelial Cells; FDA approved; Fluid Balance; Foundations; Genetic; Genetic Diseases; Genotype; Goals; Gold; Homozygote; Hospitals; Human; Image; Individual; Ion Channel; Ion Transport; Knowledge; Lead; Literature; Measures; Medical center; Mentors; Mentorship; Modeling; Molecular; Mutation; Nasal Epithelium; Nose; Pathway interactions; Patient Care; Patients; Pediatric Hospitals; Persons; Pharmaceutical Preparations; Pharmacology; Phenotype; Physicians; Population; Positioning Attribute; Pre-Clinical Model; Preclinical Testing; Process; Proteins; Pulmonology; Research; Research Design; Research Personnel; Resolution; Resources; Scientist; Sodium Chloride; Spirometry; Subgroup; Surface; Techniques; Testing; Tissues; Training; Translating; Translations; Validation; Work; base; bronchial epithelium; career; career development; clinical care; clinical efficacy; clinical phenotype; clinical predictors; cystic fibrosis patients; design; didactic education; disease-causing mutation; experience; hands-on learning; improved; improved functioning; in vivo; individual response; insight; mutant; novel; patient oriented; patient response; personalized care; personalized medicine; pre-clinical; precision medicine; predictive test; recruit; research and development; responders and non-responders; response; secondary analysis; secondary endpoint; skills; success; tool; transcriptome sequencing; treatment choice

PROJECT SUMMARY / ABSTRACT Cystic Fibrosis (CF) is the most common fatal genetic disease in Caucasians. CF is caused by mutations in the protein encoding the CF Transmembrane conductance Regulator (CFTR), an ion channel responsible for salt and fluid homeostasis in epithelial tissues. Drugs targeting mutant CFTR, termed “modulators,” hold promise as disease-modifying therapies, but are limited to genotype-specific CF subpopulations. Moreover, extensive and poorly understood subject-to-subject variability in drug response within these populations exists. Both limitations may be overcome through the use of personalized model systems of CFTR function and modulation. The proposed research seeks to validate the use of patient-derived models to predict and understand modulator response. This is a significant milestone towards the ultimate goal of using this approach to drive personalized, precision medicine in CF and to advance biochemical understanding of CFTR modulation. This proposal tests the overall hypothesis that nasal cell models can provide high-fidelity insights into modulator responses in vivo. Pediatric subjects homozygous for F508del CFTR or with a rare CFTR mutation will be recruited from an ongoing study providing robust phenotyping of their clinical response to CFTR modulators. Nasal cells will be cultured and analyzed ex vivo, and compared to the clinical response in each subject. Aim 1 of this proposal tests whether these model systems will predict subjects’ clinical response at the individual level. Aim 2 will then categorize clinical response into responder/non-responder groups and use these nasal cell model systems to investigate primary cellular mechanisms responsible for differential responses. Together, these studies will provide a vertical step towards translation of patient-derived models to inform clinical care and optimize modulator therapies. The PI for this proposal, Dr. Brewington, is an investigator in Pulmonary Medicine with a focus on personalized medicine in CF. He has personally generated the nasal cell model systems and data underlying this proposal. The mentorship team for this proposal includes complimentary expertise in translational CF research (Dr. J.P. Clancy, primary mentor), CFTR biology (Dr. Anjaparavanda Naren, Co-mentor), and research design and execution (Dr. Raouf Amin, Co-mentor). All three have a track record of mentoring success and are dedicated to the proposed work and the PI’s research development. The career development portion of this proposal is foundational to the PI’s transition to research independence, capitalizing on the extensive resources available at Cincinnati Children’s Hospital Medical Center. A combination of formal didactics, direct mentorship, and hands-on experiences will expand Dr. Brewington’s skills in the execution of patient-centered translational research, including analysis of clinical data, model system validation, and advanced biochemical techniques. This training and mentorship will be critical to Dr. Brewington realizing his goal of leading a robust, impactful, and independent research career.

项目总结/摘要 囊性纤维化（CF）是白种人最常见的致命性遗传病。CF是由基因突变引起的， 编码CF跨膜电导调节器（CFTR）的蛋白质，CFTR是一种负责盐的离子通道 和上皮组织中的流体稳态。靶向突变CFTR的药物，称为“调节剂”，有望成为 疾病修饰疗法，但限于基因型特异性CF亚群。此外，广泛和 在这些人群中，药物应答的受试者间差异性知之甚少。两种限制 可以通过使用CFTR功能和调制的个性化模型系统来克服。 拟议的研究旨在验证使用患者衍生模型来预测和理解调节剂 反应这是一个重要的里程碑，朝着使用这种方法来推动个性化， 精确医学在CF和推进CFTR调节的生化理解。该提案测试 总体假设，鼻细胞模型可以提供高保真度的见解，在体内的调制器的反应。 F508 del CFTR纯合子或具有罕见CFTR突变的儿科受试者将从正在进行的研究中招募。 研究提供了其对CFTR调节剂的临床应答的稳健表型。将培养鼻细胞 离体分析，并与每个受试者的临床反应进行比较。本提案的目标1测试是否 这些模型系统将在个体水平上预测受试者的临床反应。目标2将分类 临床反应分为应答者/非应答者组，并使用这些鼻细胞模型系统来研究 主要的细胞机制，负责不同的反应。总之，这些研究将提供一个垂直的 进一步转化患者衍生模型，为临床护理提供信息并优化调节剂治疗。 该提案的PI，Brewington博士，是肺部医学的研究者，专注于个性化 医学在CF他亲自生成了鼻细胞模型系统和支持该提议的数据。 本提案的导师团队包括翻译CF研究方面的补充专业知识（J. P. Clancy，主要导师），CFTR生物学（Anjaparavanda Naren博士，共同导师），以及研究设计和 执行（Raouf Amin博士，共同导师）。这三个人都有指导成功的记录， 建议的工作和PI的研究进展。 该提案的职业发展部分是PI向研究独立过渡的基础， 利用辛辛那提儿童医院医疗中心的广泛资源。的组合 正式的教学法，直接指导和实践经验将扩大博士。 执行以患者为中心的转化研究，包括临床数据分析，模型系统验证， 和先进的生化技术。这种培训和指导对于Brewington博士意识到 他的目标是领导一个强大的，有影响力的，独立的研究生涯。