Novel Therapies for Muco-Obstructive Lung Diseases

描述（由申请人提供）： 主要的人类气道疾病，包括CORD和CF，表现出粘液阻塞气道管腔。该tPPG基于以下前提：需要新的生物物理和生物化学假设来充分描述健康状态下的气道粘液转运，预测系统在疾病中如何以及何时失效，并发明治疗这些气道疾病的新疗法。我们假设有效和特异性的治疗将需要双重治疗活性：1）粘液“水合”活性;和2）“粘液溶解”活性，即，降低粘液凝聚和/或粘附的试剂。该tPPG应用程序介绍了三个项目和五个核心，旨在提供治疗粘膜阻塞性疾病的新疗法的科学依据、生物标志物和测试。管理核心（核心A）将监督物理和生物科学的融合，这是我们解决这一问题的基础，用于测试新治疗策略的关键临床前模型，以及临床试验，以实现我们的总体目标：1）在人类受试者中测试新型输送设备和单一/组合疗法，重点是气道补液;和2）开发新的粘液溶解平台并测试粘蛋白基因转录的抑制剂。因此，核心A将监督三个项目：1）“粘液水合和粘附/凝聚力的生物物理学”-Michael Rubenstein博士，P.I.; 2)“用于生物标志物和药物开发的粘液阻塞小鼠”- Richard Boucher，医学博士，P.I.; 3)“靶向COPD中的粘液清除缺陷”- Scott唐纳森，医学博士，P.I.核心A将监督四个核心：1）核心B（生物统计和数据管理核心）; 2）核心C 3）核心D [药代动力学/药效学（PK/PD）核心]，其将提供用于测试局部粘膜活性剂的活性的一系列PK/PD方法;和4）核心E（化合物/组合选择核心）-其将提供体外和动物模型筛选。总之，整合tPPG的活动，为启动新型给药装置的临床研究、测试水合剂的组合以及开发用于治疗COPD的新型粘液溶解药物提供科学依据。

DESCRIPTION (provided by applicant): Major human airways diseases, including CORD and CF, exhibit obstruction of airway lumens with mucus. This tPPG is based on the premise that novel biophysical and biochemical hypotheses are required to adequately describe airway mucus transport in health, predict how and when the system fails in disease, and invent novel therapies to treat these ainways diseases. We hypothesize that effective and specific therapies will require dual therapeutic activities: 1) a mucus "hydrating" activity; and 2) a "mucolytic" activity, i.e., an agent that wil decrease mucus cohesion and/or adhesion. This tPPG application presents three Projects and five Cores designed to provide the scientific basis, biomarkers, and tests of novel therapies to treat muco-obstructive diseases. The Administrative Core (Core A) will oversee the fusion of physical and biological sciences that underpins our attack on this problem, key pre-clinical models for testing novel therapeutic strategies, and clinical trials to accomplish our overarching goals of: 1) testing in human subjects novel delivery devices and single/combination therapies focused on airway re-hydration; and 2) developing a novel mucolytic platform and testing inhibitors of mucin gene transcription. Thus, Core A will oversee three Projects: 1) "The Biophysics of Mucus Hydration and Adhesion/Cohesion" -Michael Rubenstein, Ph.D., P.I.; 2) "Mucus Obstructed Mice for Biomarker and Drug Development" - Richard Boucher, M.D., P.I.; 3) "Targeting Defective Mucus Clearance in COPD" - Scott Donaldson, M.D., P.I. Core A will oversee four Cores: 1) Core B (the Biostatistics and Data Management Core); 2) Core C (the Mucus Core), which will provide state-of-the-art measurements of mucin concentration/biophysical properties; 3) Core D [the Pharmacokinetics/Pharmacodynamics (PK/PD) Core], which will provide a range of PK/PD methodologies for testing activities of topical muco-active agents; and 4) Core E (the Compound/Combination Selection Core) - which will provide in vitro and animal model screens. In sum, the activities of the tPPG are integrated to provide the scientific bases to initiate clinical studies of novel delivery devices, to test combinations of hydrating agents, and to develop a new mucolytic drug for therapy of COPD.