Perinatal Origins of Chronic Mountain Sickness

描述（由申请人提供）：父母资助（NIH RO 1 HL 079647“缺氧诱导的宫内生长受限（IUGR）的遗传调控”）测试了缺氧诱导转录（HIF）靶向或调控途径中的遗传变异保护多代高海拔居民免受缺氧相关IUGR的总体假设。系列研究提出在怀孕期间和产后100高（3600米）和100低（300米）海拔居民，分为多代高海拔（安第斯山脉）或低海拔（欧洲）血统的妇女。具体目的测试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血流和胎儿生长变异性，以及3）HIF调节基因影响UA血管收缩、血管舒张、或生长有助于安第斯人与欧洲人对怀孕的母体生理反应的变化。在这个FIRCA中，我们建议扩展我们的研究，以测试这一假设，即在缺氧环境中妊娠和出生会导致呼吸和肺结构控制的终身改变，随之而来的功能改变会增加成年后对慢性高山病（CMS）的易感性。我们将胎儿起源假说扩展到肺循环和/或呼吸控制异常的具体目标是：1）表征具有升高的血红蛋白水平或过度红细胞增多症（EE）（CMS的早期形式）的年轻成人的表型，关于a）在觉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，以及2）通过将EE个体与一组健康对照者就其经历a）胎儿生长减少，B）先兆子痫，c）新生儿缺氧的患病率进行比较，确定EE个体在围产期是否更缺氧。我们和其他人最近的工作支持了EE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）高海拔居民（e3600米）; 75名EE和75名健康对照。根据年龄和居住海拔匹配的受试者将在睡眠和觉醒期间的呼吸控制、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。将进行访谈和病历审查，以评估围产期慢性缺氧或胎儿生长减少与成年EE之间的关系。将酌情使用一系列逻辑和线性回归分析确定这些母体和围产期特征、呼吸功能、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。了解CMS的起源将有助于早期识别和预防这一公共卫生问题，该问题影响约10%的成年男性，或全球1000万人，并构成南美，亚洲和美国高原地区发病率和死亡率的主要原因。绩效地点（组织、城市、州）美国地点：国外地点：Lorna G.摩尔，博士恩里克巴尔加斯，医学博士海拔研究中心玻利维亚生物学研究所阿尔图拉大学科罗拉多丹佛Edificio IBBA - Calle Claudio Sanjmnes s/n Frente al Torax，米拉弗洛雷斯;拉巴斯，玻利维亚关键人员：Lorna G.摩尔博士科罗拉多大学丹佛分校PI恩里克·巴尔加斯博士玻利维亚生物学研究所阿尔图拉外国合作者Colleen Glyde Julian博士科罗拉多大学丹佛分校共同研究员大卫Lynch博士国家犹太医学和研究中心共同研究员Daniela Davila博士玻利维亚生物学研究所阿尔图拉共同研究员Susan Niermeyer博士科罗拉多大学丹佛分校顾问Teofilo Lee-Chiong博士医学博士国家犹太医学和研究中心顾问John Kittelson，博士科罗拉多丹佛大学顾问Joe McCord，博士科罗拉多丹佛大学顾问公共卫生相关：CMS是一种常见但知之甚少的疾病，影响全球多达1000万人。它没有已知的补救措施，除了下降到较低的海拔，并可能导致肺动脉高压和右心衰竭死亡。我们提出的研究提出了新的问题，CMS是否有围产期起源。如果是这样，可以设计干预和/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.