Novel Therapies for Muco-Obstructive Lung Diseases

描述(由申请人提供)： 主要的人类呼吸道疾病，包括脐带和CF，表现为粘液阻塞气道腔。这一tPPG的前提是需要新的生物物理和生化假说来充分描述健康中的呼吸道粘液运输，预测系统在疾病中如何以及何时失效，并发明新的治疗方法来治疗这些主要疾病。我们假设，有效和特定的治疗方法需要双重治疗活动：1)粘液“补水”活性；2)“粘液溶解”活性，即降低粘液凝聚力和/或粘附性的制剂。这项tPPG应用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基础、生物标记物和测试。行政核心(核心A)将监督支持我们解决这一问题的物理和生物科学的融合、测试新型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)在人体受试者中测试新型给药装置和专注于呼吸道再水化的单一/组合疗法；以及2)开发新型粘蛋白溶解平台和测试粘蛋白基因转录的抑制物。因此，核心A将监督三个项目：1)“粘液水化和粘连/凝聚力的生物物理学”--Michael Rubenstein，Ph.D.，P.I.；2)“粘液阻挡小鼠的生物标记物和药物开发”--Richard Boucher，M.D.，P.I.；3)“针对慢性阻塞性肺疾病的粘液清除”--Scott Donaldson，M.D.，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)Core C(粘液核心)，将提供最先进的粘蛋白浓度/生物物理性质测量；3)Core D[药代动力学/药效学(PK/PD)核心]，将为测试局部粘液活性提供一系列PK/PD方法；以及4)Core E(化合物/组合选择核心)，将提供体外和动物模型筛选。总之，tPPG的活性被整合起来，为启动新型给药装置的临床研究、测试水剂的组合以及开发治疗COPD的新的粘液溶解药物提供科学基础。

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.