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

项目摘要/摘要 囊性纤维化是高加索人最常见的致死性遗传病。Cf由基因突变引起 编码Cf跨膜电导调节器(CFTR)的蛋白质，这是一个负责盐的离子通道 和上皮组织中的液体动态平衡。针对突变cftr的药物，被称为“调节器”，有希望成为 疾病修饰疗法，但仅限于特定于基因型的CF亚群。此外，广泛和广泛的 在这些人群中，药物反应的受试者对受试者的可变性知之甚少。这两个限制 可以通过使用个性化的CFTR功能和调制模型系统来克服。 这项拟议的研究试图验证使用患者衍生模型来预测和理解调节器 回应。这是一个重要的里程碑，朝着使用这种方法推动个性化的最终目标迈进， 精准医学在CFR中的应用，促进对CFTR调控的生物化学理解。这份提案测试了 鼻腔细胞模型可以提供体内调节器反应的高保真洞察力的总体假设。 F508del 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 研究提供了他们对CFTR调节剂的临床反应的稳健表型。鼻腔细胞将被培养 并进行体外分析，比较各受试者的临床反应。该提案的目标1测试是否 这些模型系统将在个体层面预测受试者的临床反应。然后Aim 2将对 临床反应进入应答者/无应答者组，并使用这些鼻腔细胞模型系统来研究 负责差异反应的主要细胞机制。总而言之，这些研究将提供垂直的 逐步翻译患者衍生的模型，为临床护理提供信息，并优化调节剂疗法。 这项提议的私人投资，布雷温顿博士，是一名肺部医学的研究员，专注于个性化 CF中的医学。他亲自生成了支撑这一提议的鼻细胞模型系统和数据。 这项建议的指导团队包括翻译CF研究方面的免费专业知识(J.P. Clancy，主要导师)，CFTR生物学(Anjparavanda Naren博士，共同导师)，以及研究设计和 执行(Raouf Amin博士，共同导师)。这三个人都有成功指导的记录，而且都很敬业 对提出的工作和PI的研究进展进行了展望。 这项提议的职业发展部分是私人投资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。一种组合 正式的教学、直接的指导和实践经验将扩展Brewington博士在 执行以患者为中心的转化性研究，包括临床数据分析、模型系统验证、 和先进的生化技术。这种培训和指导将对布雷温顿博士实现 他的目标是领导一个强大的、有影响力的和独立的研究事业。

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.