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限制（IUGR）的遗传调控”）测试了总体假设，即低氧诱导转录（HIF）目标或调控途径中的遗传变异保护多代高海拔居民免受低氧相关的IUGR。在怀孕和产后对100名高海拔（3600米）和100名低海拔（300米）居民进行了系列研究，这些居民分为多代高海拔（安第斯）或低海拔（欧洲）血统的妇女。特异性目的测试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血流和胎儿生长变变性；3)影响UA血管收缩、血管舒张或生长的hif调节基因有助于安第斯人和欧洲人怀孕时母体生理反应的差异。在本FIRCA中，我们建议扩展我们的研究，以验证在缺氧环境中妊娠和出生会导致呼吸和肺结构控制终身改变的假设，随之而来的功能改变会增加成年后对慢性高原病（CMS）的易感性。我们的具体目标，将胎儿起源假说扩展到肺循环异常和/或呼吸控制，是1)表征具有血红蛋白水平升高或过度红细胞增多（EE）的年轻人的表型，这是CMS的早期形式，涉及a)清醒和睡眠期间呼吸控制，b)肺结构和功能。c)肺循环和d)氧化还原状态，以及2)通过与健康对照组比较，确定EE个体在围产期是否更容易缺氧，他们经历的患病率为a)胎儿生长减少，b)先兆子痫，c)新生儿缺氧。我们和其他人最近的工作支持提出的假设，即情感表达有围产期起源。该研究将确定150名高海拔地区（海拔3600m）的男性（15-25岁）居民；75名情感障碍患者和75名健康对照者。受试者根据年龄和居住海拔进行匹配，比较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。访谈和病历回顾将用于评估围产期慢性缺氧或胎儿生长降低与成年期EE之间的关系。这些产妇和围产期特征、通气功能、肺结构和肺循环异常、氧化还原状态和成年期EE之间的关系将酌情使用一系列逻辑和线性回归分析来确定。了解CMS的起源将有助于早期认识和预防这一公共卫生问题，该问题影响到全球约10%的成年男性，或1000万人，是南美洲，亚洲和美国高地地区发病率和死亡率的主要原因。演出地点(S)（组织、城市、州）美国地点：国外地点：Lorna G. Moore，博士Enrique Vargas，医学博士海拔研究中心Instituto Boliviano de Biologma de Altura科罗拉多大学丹佛Edificio IBBA - Calle Claudio Sanjmnes /n Frente al Torax， Miraflores；拉巴斯，玻利维亚Lorna G. Moore博士，科罗拉多大学丹佛分校PI Enrique Vargas博士，玻利维亚生物研究所外国合作者Colleen Glyde Julian博士，科罗拉多大学丹佛分校联合研究员David Lynch博士，国家犹太医学研究中心联合研究员Daniela Davila博士，玻利维亚生物研究所联合研究员Susan Niermeyer博士，科罗拉多大学丹佛分校顾问Teofilo Lee-Chiong，国家犹太医学和研究中心顾问John Kittelson博士，科罗拉多大学丹佛顾问Joe McCord博士，科罗拉多大学丹佛顾问公共卫生相关性：CMS是一种常见但知之甚少的疾病，影响全球多达1000万人。目前没有已知的治疗方法，只能下降到较低的海拔，并可导致肺动脉高压和右心衰死亡。我们提出的研究提出了一个新的问题，即CMS是否有围产期起源。如果是这样，就可以设计干预措施和/或更有效的治疗方法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.