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

这份申请为A·科特尼·亨德森博士提出了一份职业发展计划。作为博士后研究员 与导师Kim Prisk博士合作，她研究了肺水和重力对肺组织分布的影响。 用核磁共振检查肺血流量。在K99阶段，她学会了如何应用多重惰性气体 Peter博士指导下慢性阻塞性肺疾病(COPD)患者的排泄技术(MIGET) 瓦格纳(共同导师)。加州大学圣迭戈分校的研究环境非常好， 约翰·韦斯特博士和彼得·瓦格纳博士的领导力在30多年里一直是世界上最好的 好几年了。拟议的研究计划将研究与气体交换相关的生理机制。 COPD的缺陷，其特征是通气量/灌注率(VA/Q)不相等。缺氧性肺 血管收缩(HPV)可减少COPD患者的VA/Q错配。总体假设是，总体上不同 Va/Q不等、通风和血流的空间模式以及HPV对HPV分布的影响 COPD的血流反映了疾病主要是肺气肿(肺组织破坏)还是 主要是呼吸道疾病。肺血流、通气量和VA/Q的空间分布将是 使用MRI测量和使用MIGET测量总体VA/Q不等性。慢性阻塞性肺疾病患者表现为 以肺气肿或以呼吸道疾病为主的健康受试者将是 在呼吸空气的同时研究，然后吸入高氧气体来缓解HPV。以下关键假设将是 结果：(1)在肺气肿患者中，低灌注是导致高VA/Q区的主要原因 由于肺组织和毛细血管破坏，其空间分布是决定 呼吸机和血流的异质性，(2)在以呼吸道疾病为主的患者中，以 低VA/Q区的原因是由于支气管阻塞导致的低通气量以及(3) 人乳头状瘤病毒是导致总的VA/Q不平等和空间异质性的重要机制 血液流动的速度。我们正在与加州大学圣迭戈分校临床研究中心的Joe Ramsdell医学博士合作，为多中心 由NIH资助的COPD遗传流行病学(COPDgene)项目，提供了对大型 具有良好特征的COPD患者的数量。COPD基因研究的总体目标是确定 慢性阻塞性肺疾病的遗传危险因素。COPDgene的目标与这一提议高度协同，从而允许 用于根据生理机制表征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.