Perinatal Origins of Chronic Mountain Sickness

描述(由申请人提供)：父母资助(NIH RO1 HL079647“低氧诱导的宫内生长受限(IUGR)的遗传调节”)测试了低氧诱导转录(HIF)靶向或调控途径中的基因变异保护多代高海拔居民免受低氧相关IUGR的总体假设。在孕期和产后对100名高海拔(3600米)和100名低海拔(300米)居民进行了一系列研究，分为多代高海拔(安第斯)或低海拔(欧洲)血统的妇女。具体目的是测试1)安第斯血统是否由于影响HIF靶向基因产物和子宫动脉(UA)血流的遗传因素而对缺氧诱导的IUGR具有保护作用，2)HIF靶向和调节基因有助于UA血流和胎儿生长变异性，以及3)HIF调节基因影响UA血管收缩、血管扩张或生长导致安第斯人与欧洲人怀孕后母亲生理反应的差异。在这项FIRCA中，我们建议扩展我们的研究，以检验这一假设，即在低氧环境中怀孕和出生会导致呼吸和肺结构控制的终身改变，从而导致功能改变，增加成年后患慢性高原病(CMS)的易感性。我们的具体目标是将胎儿起源假说扩展到肺循环异常和/或呼吸控制，1)表征血红蛋白水平升高或红细胞过度增多(EE)的年轻人的表型，这是CMS的一种早期形式，涉及a)清醒和睡眠期间的呼吸控制，b)肺结构和功能，c)肺循环和d)氧化还原状态，2)通过比较EE患者和一组健康对照组的患病率，确定EE患者在围产期是否更缺氧。我们和其他人最近的工作支持了EE具有围产期起源的假设。这项拟议的研究将确定150名男性(15-25岁)居住在高海拔地区(e3600米)；75名患有EE和75名健康对照。与年龄和居住海拔相匹配的受试者将在睡眠和清醒时的呼吸控制、肺结构和功能、肺循环、氧化还原状态和血液学特征方面进行比较。将进行访谈和病历回顾，以评估围产期慢性缺氧或成年期胎儿发育减退与EE的关系。这些母亲和围产儿特征、呼吸功能、肺结构和肺循环异常、氧化还原状态和成年后EE之间的关系将使用一系列Logistic和线性回归分析来确定。了解CMS的起源将有助于及早认识和可能预防这一公共卫生问题。这一公共卫生问题影响着约10%的成年男性，即全球1000万人，是南美洲、亚洲和美国高原地区发病率和死亡率的主要原因。演出站点(S)(组织，城市，州)美国站点：国外站点：洛娜·G·摩尔，博士恩里克·瓦尔加斯，科罗拉多大学阿尔图拉大学医学海拔研究中心玻利维亚生物研究所，伊巴-卡莱·克劳迪奥·桑杰曼斯S/n Frente al Torax，Miraflres；玻利维亚拉巴斯主要人员：洛娜·G·摩尔，科罗拉多大学博士，丹佛·皮恩里克·巴尔加斯博士，科罗拉多玻利维亚生物研究院医学博士，科罗拉多大学外国合作者Colleen Glyde Julian，科罗拉多大学丹佛博士共同研究员David Lynch，MD国家犹太医学和研究中心共同研究员Daniela Davila，MD丹佛医学研究所共同研究员Susan Niermeyer，MD丹佛大学顾问Teofilo Lee-Chiong，MD国家犹太医学和研究中心顾问John Kittelson，科罗拉多大学博士顾问Joe McCord，科罗拉多大学丹佛分校公共卫生相关：CMS是一种常见但鲜为人知的疾病，影响到全球1,000万人。除了下降到较低的海拔，它还没有已知的治疗方法，可能会导致肺动脉高压和右心衰竭死亡。我们提出的研究提出了一个新的问题，即CMS是否起源于围产期。如果是这样的话，可以设计干预措施和/或更有效的治疗来治愈并最终预防这种疾病。

DESCRIPTION (provided by applicant): The parent grant (NIH RO1 HL079647 "Genetic Regulation of Hypoxia-Induced Intrauterine Growth Restriction (IUGR)") tests the overall hypothesis that genetic variants in hypoxia-inducible transcription (HIF)-targeted or regulatory pathways protect multigenerational high-altitude residents from hypoxia-associated IUGR. Serial studies are proposed during pregnancy and postpartum in 100 high- (3600 m) and 100 low- (300 m) altitude residents, divided between women of multigenerational high-altitude (Andean) or low-altitude (European) ancestry. Specific aims test whether 1) Andean ancestry is protective against hypoxia-induced IUGR due to genetic factors influencing HIF-targeted gene products and uterine artery (UA) blood flow, 2) HIF-targeted and -regulatory genes contribute to UA blood flow and fetal growth variability and 3) HIF-regulated genes influencing UA vasoconstriction, vasodilation, or growth contribute to the variation in maternal physiologic responses to pregnancy in Andeans vs. Europeans. In this FIRCA, we propose to extend our studies to test the hypothesis that gestation and birth in a hypoxic environment result in lifelong alterations in control of breathing and lung structure, with consequent functional alterations that increase susceptibility to Chronic Mountain Sickness (CMS) in adulthood. Our specific aims, which extend the fetal origins hypothesis to abnormalities of the pulmonary circulation and/or control of breathing, are to 1) characterize the phenotype of young adults with elevated hemoglobin levels or excessive erythrocytosis (EE), an early form of CMS, with respect to a) control of breathing during wakefulness and sleep, b) lung structure and function, c) pulmonary circulation and d) redox status and to 2) establish whether individuals with EE were more hypoxic during perinatal life by comparing them with a group of healthy controls with respect to the prevalence with which they experienced a) fetal growth reduction, b) preeclampsia, c) neonatal hypoxia. Our and others' recent work support the proposed hypothesis that EE has perinatal origins. The proposed study will identify 150 male (aged 15-25) residents of high altitudes (e3600m); 75 with EE and 75 healthy controls. The subjects, matched by age and altitude of residence, will be compared with respect to control of breathing during sleep and wakefulness, lung structure and function, pulmonary circulation, redox status and hematological characteristics. Interviews and medical-record reviews will be conducted to evaluate the relationship between chronic hypoxia during the perinatal period or reduced fetal growth and EE in adulthood. The relationship between these maternal and perinatal characteristics, ventilatory function, lung structure and pulmonary circulation abnormalities, redox status and EE in adulthood will be determined using a series of logistic and linear regression analyses, as appropriate. Understanding the origins of CMS will aid in the early recognition and possible prevention of this public health problem which affects ~ 10% of adult men, or 10 million persons worldwide and constitutes a major cause of morbidity and mortality in the highland regions of South America, Asia and the United States. PERFORMANCE SITE(S) (organization, city, state) USA site: Foreign site: Lorna G. Moore, PhD Enrique Vargas, MD Altitude Research Center Instituto Boliviano de Biologma de Altura University of Colorado Denver Edificio IBBA - Calle Claudio Sanjmnes s/n Frente al Torax, Miraflores; La Paz, Bolivia KEY PERSONNEL: Lorna G. Moore, PhD University of Colorado Denver PI Enrique Vargas, MD Instituto Boliviano de Biologma de Altura Foreign Collaborator Colleen Glyde Julian, PhD University of Colorado Denver Co-investigator David Lynch, MD National Jewish Medical and Research Center Co-investigator Daniela Davila, MD Instituto Boliviano de Biologma de Altura Co-investigator Susan Niermeyer, MD University of Colorado Denver Consultant Teofilo Lee-Chiong, MD National Jewish Medical and Research Center Consultant John Kittelson, PhD University of Colorado Denver Consultant Joe McCord, PhD University of Colorado Denver Consultant PUBLIC HEALTH RELEVANCE: CMS is a common but poorly understood disorder affecting up to 10 million persons worldwide. It has no known remedy, except descent to lower altitudes, and can result in death from pulmonary hypertension and right heart failure. Our proposed studies pose the novel question as to whether CMS has perinatal origins. If so, interventions and/or more effective treatments can be designed to cure and ultimately prevent this disorder.