Influence of spatial patterns of ventilation & perfusion on gas exchange in COPD

这份申请书为A博士提出了一个职业发展计划。科特尼亨德森。担任博士后研究员 与Kim Prisk博士（导师）合作，她研究了肺水和重力对肺组织分布的影响。 肺血流量在K99阶段，她学会了如何使用多种惰性气体 慢性阻塞性肺疾病（COPD）患者中的MIGET 瓦格纳（共同导师）。UCSD的研究环境非常好，生理学部门 30多年来，约翰·韦斯特博士和彼得·瓦格纳博士的领导一直是世界上最好的领导之一。 年拟议的研究计划将研究与气体交换有关的生理机制 COPD的特征在于通气-灌注比（VA/Q）不平等。低氧性肺动脉 血管收缩（HPV）减少COPD中的VA/Q失配。总的假设是， VA/Q不等式、通气和血流的空间模式以及HPV对肺动脉高压分布的影响 COPD中的血流反映疾病是否主要是肺气肿（肺组织破坏）或 主要是呼吸道疾病。肺血流量、通气量和VA/Q的空间分布将如下所示： 使用MRI测量的VA/Q不平等和使用MIGET测量的总体VA/Q不平等。COPD患者表现为 主要为肺气肿或主要为气道疾病的受试者和年龄匹配的健康受试者将 研究同时呼吸空气，然后高氧气体，以减轻HPV。以下主要假设将是 经检验：（1）在以肺气肿为主的患者中，高VA/Q区域的主要原因是低灌注 由于肺组织和毛细血管的破坏，其空间分布是一个重要的决定因素， 通气和血流的异质性，（2）在气道疾病为主的患者中， 低VA/Q区域的原因是由于支气管阻塞引起的低通气，以及（3） HPV是导致VA/Q不平等和空间异质性的重要机制 血液流动。我们正在与医学博士乔·拉姆斯德尔合作，UCSD临床研究中心多中心PI 由NIH资助的COPD遗传流行病学（COPDGene）项目，提供了大量 特征良好的COPD患者数量。COPDGene研究的总体目标是确定 COPD的遗传风险因素COPDGene的目标与这一提议高度协同，因此允许 用于基于生理机制表征COPD的亚型。

This application proposes a career development plan for Dr. A. Cortney Henderson. As a postdoctoral fellow working with Dr. Kim Prisk (mentor), she studied the effects of lung water and gravity on the distribution of pulmonary blood flow using MRI. During the K99 phase, she learned how to apply the multiple inert gas elimination technique (MIGET) in chronic obstructive pulmonary disease (COPD) patients under Dr. Peter Wagner (co-mentor). The research environment at UCSD is excellent, and the Division of Physiology under the leadership of Dr. John West and Dr. Peter Wagner has been among the best in the world for over 30 years. The proposed research plan will study physiological mechanisms associated with the gas exchange defects in COPD, which is characterized by ventilation-perfusion ratio (VA/Q) inequality. Hypoxic pulmonary vasoconstriction (HPV) reduces VA/Q mismatch in COPD. The overall hypothesis is that differing overall VA/Q inequalities, spatial patterns of ventilation and blood flow, and effects of HPV on the distribution of blood flow in COPD reflect whether the disease is predominantly emphysema (lung tissue destruction) or predominantly airway disease. The spatial distribution of pulmonary blood flow, ventilation, and VA/Q will be measured using MRI and overall VA/Q inequality measured using MIGET. COPD patients presenting with predominantly emphysema or predominantly airway disease and age-matched healthy subjects will be studied while breathing air and then a hyperoxic gas to alleviate HPV. The following key hypotheses will be tested: (1) in emphysema predominant patients, the primary cause of regions of high VA/Q is low perfusion due to lung tissue and capillary destruction, the spatial distribution of which is an important determinant of the heterogeneity of ventilation and blood flow, (2) in airway disease predominant patients, the primary cause of regions of low VA/Q is low ventilation due to bronchial obstruction, and (3) the spatial pattern of HPV is an important mechanism contributing to the type of overall VA/Q inequality and spatial heterogeneity of blood flow. We are collaborating with Joe Ramsdell, M.D., UCSD Clinical Study Center PI for the multicenter Genetic Epidemiology of COPD (COPDGene) project funded by NIH, providing access to a large number of well-characterized COPD patients. The overall goal of the COPDGene study is to identify the genetic risk factors in COPD. The aims of COPDGene are highly synergistic with this proposal, thus allowing for characterization of the subtypes of COPD based on physiological mechanisms.