Basic and Translational Studies of Cystic Fibrosis

描述（由申请人提供）：匹兹堡大学囊性纤维化研究中心（CFRC）由来自10个部门的约50名教职员工组成，提供基础和临床研究人员的研究优势。它每年获得超过1300万美元的校外赠款和合同，以支持其CF研究工作。他们专注于三大科学主题。该中心有一个强大的基础和临床前科学组成部分，解决CF和CFTR的细胞和分子生物学，并得到NIH，NSF和囊性纤维化基金会（CFF）的资助。该组中的研究者广泛使用分化的原代人支气管上皮细胞（HBE）和最近的人鼻上皮细胞（HNE）来定义CFTR运输、气道液体运输和粘膜纤毛清除中的重要步骤。这些研究旨在阐明野生型CFTR与其或多或少常见的疾病突变体以及CFTR相关转运蛋白（包括ENaC和SLC 26 A9）的功能特性。P30研究人员正在确定它们对ER蛋白生物发生和质量控制的影响，ER后运输及其对气道表面液体体积和组成的调节的影响，这些研究旨在促进 治疗学发展。技术专长和具有特定突变的HBE正在提供给学术和工业合作伙伴，用于开发目前可供患者使用或正在进行临床评估的药物。该中心的感染和免疫部分侧重于气道细菌和病毒感染，它们的相互作用，以及先天性和适应性免疫的机制，使用HBE和动物模型。这些研究旨在提高我们对CF疾病发病机制中炎症反应的理解，定义生物标志物和结局指标以改善临床试验，并确定抗炎治疗的靶点，通常通过工业相互作用。第三，转化/临床研究部分将临床前发现转化为新的治疗方法。它开发和评估方法，以改善和标准化气道药物输送，体内同位素清除和液体吸收测定，并测试针对CF核心缺陷的治疗方法。拟议的CF研究和翻译核心中心（P30）由Raymond Frizzell博士领导，Jay Kolls博士和Joseph Pilewski博士担任副主任。该中心由三个科学核心组成，支持其庞大的研究基础：人类气道细胞和测定（Frizzell和Pilewski博士，PI），转化/临床研究（Pilewski和Kolls博士，PI）和成像（Simon Watkins博士，PI）。在上一个资助期间，核心相关研究人员开发了几种新的检测方法。核心中心开展了一项试点和可行性计划，以启动新的研究人员进入CF研究，并促进既定科学家和临床医生追求新的重要想法。该中心强调将基础知识转化为应用疗法。

DESCRIPTION (provided by applicant): The Cystic Fibrosis Research Center (CFRC) at the University of Pittsburgh is comprised of ~50 faculty members from ten departments, providing research strengths from basic and clinical investigators. It garners more than $13 M/yr in extramural grants and contracts to support its CF research efforts. They are focused on three major scientific themes. The Center has a strong basic and pre-clinical science component that addresses the Cell and Molecular Biology of CF and CFTR, and it is supported by NIH, NSF and Cystic Fibrosis Foundation (CFF) grants. Investigators in this group make extensive use of differentiated, primary human bronchial epithelia (HBE), and more recently human nasal epithelia (HNE), to define important steps in CFTR trafficking, airway liquid transport and mucociliary clearance. These studies are directed at elucidating the functional properties of wild type CFTR in relation to its more or less common disease mutants, as well as CFTR's associated transporters, including ENaC and SLC26A9. P30 investigators are identifying their impact on ER protein biogenesis and quality control, post-ER trafficking and their impact on the regulation of airway surface liquid volume and composition, studies that are directed to facilitate therapeutics development. Technical expertise and HBE having specific mutations are being provided to academic and industrial partners for the development of drugs that are currently available to patients or are in clinical evaluations. The Infection and Immunity component of the Center focuses on airway bacterial and viral infections, their interactions, and mechanisms of innate and adaptive immunity, using HBEs and animal models. These studies aim to improve our understanding of the inflammatory response in CF disease pathogenesis, define biomarkers and outcome measures to improve clinical trials, and identify targets for anti-inflammatory therapy, often through industrial interactions. Third, the Translational/Clinical Studies component translates pre-clinical findings into new therapeutic approaches. It develops and evaluates methods to improve and standardize airway drug delivery, in vivo isotopic clearance and liquid absorption assays, and test therapeutics that target the core defect in CF. The proposed CF Research and Translation Core Center (P30) is directed by Dr. Raymond Frizzell with Drs. Jay Kolls and Joseph Pilewski serving as Associate Directors. The Center is comprised of three scientific cores that support its large research base: Human Airway Cells and Assays (Drs. Frizzell and Pilewski, PIs), Translational/Clinical Studies (Drs. Pilewski and Kolls, PIs), and Imaging (Dr. Simon Watkins, PI). In the last grant period, several new assays have been developed by core associated investigators. The Core Center operates a Pilot and Feasibility Program to initiate new investigators into CF research and to facilitate the pursuit of new important ideas by established scientists and clinicians. The Center emphasizes the translation of basic knowledge into applied therapeutics.