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

描述(由申请人提供)：此申请表为A·科特尼·亨德森博士提出了一份职业发展计划。作为一名博士后研究员，她与Kim Prisk博士(导师)一起工作，利用MRI研究了肺水和重力对肺血流分布的影响。在剩下的博士后培训中，她将学习如何在Peter Wagner博士(共同导师)的指导下，将多重惰性气体消除技术(MIGET)应用于慢性阻塞性肺疾病(COPD)患者。加州大学圣迭戈分校的研究环境一流，在约翰·韦斯特博士和彼得·瓦格纳博士的领导下，生理学部门30多年来一直是世界上最好的部门之一。拟议的研究计划将研究与COPD气体交换缺陷相关的生理机制，其特征是通风/灌流比(VA/Q)不平等。缺氧性肺血管收缩(HPV)可减少COPD患者的VA/Q不匹配。总体假设是，不同的总体VA/Q不平等、通风和血流的空间模式以及HPV对COPD血流分布的影响反映了COPD主要是肺气肿(肺组织破坏)还是以呼吸道疾病为主。使用MRI测量肺血流量、通气量和VA/Q的空间分布，并使用MIGET测量总体VA/Q不等性。主要表现为肺气肿或以呼吸道疾病为主的COPD患者和年龄匹配的健康受试者将被研究，同时呼吸空气，然后呼吸高氧气体以缓解HPV。我们将检验以下关键假设：(1)在肺气肿占优势的患者中，高VA/Q区的主要原因是肺组织和毛细血管破坏导致的低灌注，其空间分布是决定呼吸和血流异质性的重要因素；(2)在以呼吸道疾病为主的患者中，低VA/Q区的主要原因是由于支气管阻塞而导致的低通气量；(3)HPV的空间分布模式是导致总体VA/Q不均匀和血流空间不均的重要机制。我们将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，开展由NIH资助的COPD多中心遗传流行病学(COPDgene)项目，为大量具有良好特征的COPD患者提供机会。COPD基因研究的总体目标是确定COPD的遗传风险因素。COPD基因的目标与这一提议高度协同，从而允许根据生理机制表征COPD的亚型。相关性(见说明)：慢性阻塞性肺病是全球第四大死因，到2020年将成为第三大死因。联合使用MIGET和MRI来解决针对参与NIH资助的COPD基因研究的一组具有良好特征的COPD患者的拟议假设，将提供对COPD亚型潜在生理学的洞察，因此可能有助于为当前的医疗治疗选择最佳患者，并为未来的治疗提供途径。

DESCRIPTION (provided by applicant): 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 remainder of her postdoctoral training, she will learn 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 will collaborate with Joe Ramsdell, M.D., UCSD Clinical Study Center PI for the multi-center 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. RELEVANCE (See instructions): COPD is the 4th leading cause of death worldwide, and will be the 3rd leading cause of death by 2020. Combined use of MIGET and MRI to address the proposed hypotheses for a well-characterized group of COPD patients participating in the NIH-funded COPDGene study will provide insight into the underlying physiology in the subtypes of COPD, and therefore may facilitate optimal patient selection for current medical treatments as well as provide pathways for future therapies.