Mechanisms of Force Fluctuation-Induced Relengthening in Airway Smooth Muscle

描述(由申请人提供)： 本提案概述了一项为期四年的培训计划，以发展其在呼吸道平滑肌生物学方面的学术生涯。首席研究员是一位接受过成人和儿童治疗培训的肺科医生，是芝加哥大学儿科肺部内科的讲师。她的直接目标是通过结合肌肉生理学、力学和分子生物学原理来研究呼吸道平滑肌功能及其在疾病中的潜在作用，从而扩展她作为一名基础科学家的技能。我们的长期目标是成为一名出色的研究员，巧妙地研究平滑肌生理学的细微差别，探索该领域独特而重要的问题。朱利安·索尔韦博士和理查德·米切尔博士将共同指导首席研究员的科学和职业发展。索尔韦博士是呼吸道生物学和平滑肌生理学方面的专家，也是一位杰出的导师和榜样。他致力于促进首席调查员的职业发展和最终的独立性。米切尔博士是国际知名的平滑肌生理学家，也是指导实验设计和技术的宝贵资源。此外，一个由肌肉生理学和分子生物学领域的杰出科学家组成的咨询委员会将监督科学培训和职业发展。拟议的研究集中在确定调节力波动诱导的再伦化(FFIR)的分子机制上。这一建议的关键前提是：1)呼吸有助于在面临支气管收缩时维持正常的呼吸道口径，以及2)了解这种反应的分子机制将为设计新的干预措施以增强这种强大的内源性支气管扩张机制提供新的策略。在人和动物模型中，呼吸暂停都能拮抗收缩引起的气流阻塞，很可能是呼吸道平滑肌的FFIR解释了呼吸的这种抗支气管收缩作用。因此，很有兴趣知道是什么机制决定了FFIR，以及如何操纵平滑肌肉来强调这一现象。这种方法有可能成为治疗哮喘的一种新方法。这项建议的目的是加深我们对呼吸道平滑肌生物学的了解，并期望这些知识将导致对哮喘等疾病的新治疗策略。 (摘要结束)

DESCRIPTION (provided by applicant): A four year training program for the development of an academic career in airway smooth muscle biology is outlined in this proposal. The principal investigator, a pulmonologist trained to treat both adults and children, is an Instructor in the Section of Pediatric Pulmonary Medicine at the University of Chicago. Her immediate goal is to expand upon her skills as a basic scientist by combining muscle physiology, mechanics, and molecular biology principles to address airway smooth muscle function and its potential role in disease. The long term goal is to become an outstanding investigator who skillfully examines the nuances of smooth muscle physiology, exploring unique and important questions in this field. Drs. Julian Solway and Richard Mitchell will co-mentor the principal investigator's scientific and career development. Dr. Solway is an expert in airway biology and smooth muscle physiology, as well as an exceptional mentor and role model. He is committed to fostering the principal investigator's career development and ultimate independence. Dr. Mitchell is an internationally known smooth muscle physiologist and a valuable resource for guidance in experimental design and techniques. In addition, an Advisory Committee of accomplished scientists in muscle physiology and molecular biology will oversee the scientific training and career development. The proposed studies focus on identifying molecular mechanisms that regulate force fluctuation-induced relengthening (FFIR) in airway smooth muscle. The key premises underlying this proposal are that 1) breathing helps maintain normal airway caliber in the face of bronchoconstriction, and 2) understanding the molecular mechanisms underlying this response will suggest new strategies for designing novel interventions to augment this powerful endogenous bronchodilation mechanism. Hyperpnea antagonizes constrictorinduced airflow obstruction in both people and animal models and it is very likely that FFIR of airway smooth muscle accounts for this anti-bronchoconstrictor effect of breathing. Therefore, it is of considerable interest to know what mechanisms determine FFIR, and how smooth muscle might be manipulated to accentuate this phenomenon. Potentially, this approach could hold promise as a novel treatment for asthma. The goal of this proposal is to further our understanding of airway smooth muscle biology with the anticipation that such knowledge will lead to novel therapeutic strategies for diseases such as asthma (End of Abstract)