Perinatal Origins of Chronic Mountain Sickness

慢性高山病的围产期起源

基本信息

批准号：
7629545
负责人：
LORNA G. MOORE
金额：
$ 3.79万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-08 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7629545
关键词：
Adult Affect Age Altitude Altitude Sickness Arteries Asia Biological Assay Birth Blood Vessels Blood Volume Blood flow Bolivia Breathing Capital Cardiopulmonary Cessation of life Characteristics Chronic Chronic Disease Cities Colorado Country Cross-Sectional Studies Development Disease Dissociation Doctor of Philosophy Environment Environmental air flow Erythrocytoses Etiology European Fetal Growth Fetal Growth Retardation Fetus Fostering Gene Targeting Genes Genetic Genetic Transcription Genetic Variation Growth Heart failure Hemoglobin Hemoglobin concentration result High birth weight infant Human Resources Hypoxia Individual Intervention Interview Laboratories Life Linear Regressions Logistics Luciferases Lung Lung diseases Medical Records Medical Research Messenger RNA Morbidity - disease rate Morphology Natural Selections Neonatal Onset of illness Oxidation-Reduction Oxygen Oxygen measurement, partial pressure, arterial Perinatal Perinatal Hypoxia Persons Phenotype Physiological Physiological Adaptation Population Postpartum Period Pre-Eclampsia Precipitating Factors Predisposition Pregnancy Premature Birth Prevalence Prevention Process Proteins Protocols documentation Public Health Pulmonary Circulation Pulmonary Hypertension Regression Analysis Regulation Regulator Genes Regulatory Pathway Research Research Personnel Respiratory physiology Role Sea Series Single Nucleotide Polymorphism Site Sleep South America Structure Techniques Testing United States United States National Institutes of Health Universities Variant Vasodilation Wakefulness Woman Work age effect aged base design effective therapy experience fetal follower of religion Jewish genetic variant hypoxia neonatorum interest lung maturation male meetings men mortality novel parent grant performance site pre-clinical pregnant prevent promoter public health relevance residence response sex transcription factor vasoconstriction young adult

项目摘要

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.

描述（由申请人提供）：母基金（NIH RO1 HL079647“缺氧诱导的宫内生长受限（IUGR）的基因调节”）测试了总体假设，即缺氧诱导转录（HIF）靶向或调节途径中的遗传变异保护多代高海拔居民因缺氧相关的 IUGR。建议在怀孕期间和产后对 100 名高海拔（3600 m）和 100 名低海拔（300 m）居民进行系列研究，这些居民分为多代高海拔（安第斯）或低海拔（欧洲）血统的女性。具体目标测试：1) 安第斯血统是否能预防缺氧引起的 IUGR，因为遗传因素影响 HIF 靶向基因产物和子宫动脉 (UA) 血流，2) HIF 靶向和调节基因有助于 UA 血流和胎儿生长变异性和 3) 影响 UA 血管收缩、血管舒张或生长的 HIF 调节基因导致安第斯人与欧洲人对妊娠的母亲生理反应的差异。在本次 FIRCA 中，我们建议扩展我们的研究，以检验以下假设：缺氧环境中的妊娠和出生会导致呼吸和肺部结构控制的终生改变，随之而来的功能改变会增加成年期慢性高山病 (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和/或呼吸控制异常，1）表征血红蛋白水平升高或红细胞增多症（EE）（一种 CMS 的早期形式）的年轻人的表型，关于 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，以及 2) 确定 EE 患者在围产期是否更缺氧通过将他们与一组健康对照者进行比较，了解他们经历的a）胎儿生长迟缓，b）先兆子痫，c）新生儿缺氧的患病率。我们和其他人最近的工作支持了 EE 起源于围产期的假设。拟议的研究将确定 150 名高海拔地区（e3600m）男性（15-25 岁）居民； 75 名有 EE 和 75 名健康对照。根据年龄和居住海拔高度，将比较受试者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。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迟缓与成年期 EE 之间的关系。这些母体和围产期特征、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回归和线性回归分析来确定。了解 CMS 的起源将有助于及早认识并可能预防这一公共卫生问题，该问题影响约 10% 的成年男性，即全世界 1000 万人，是南美洲高地地区发病和死亡的主要原因，亚洲和美国。表演网站（组织、城市、州）美国网站：国外网站： 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 Denver Edificio IBBA - Calle Claudio Sanjmnes s/n托拉克斯阵线，米拉弗洛雷斯；玻利维亚拉巴斯主要人员： Lorna G. Moore，博士科罗拉多大学丹佛分校 PI Enrique Vargas，医学博士玻利维亚阿尔图拉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，医学博士国家犹太医学和研究中心联合研究员 Daniela Davila，医学博士 Instituto Boliviano de Biologma de Altura联合研究员 Susan Niermeyer，医学博士科罗拉多大学丹佛分校顾问 Teofilo Lee-Chiong，医学博士国家犹太医学研究中心顾问 John Kittelson，博士科罗拉多大学丹佛分校顾问 Joe McCord，博士科罗拉多大学丹佛分校顾问公共卫生相关性：CMS 是一种常见但知之甚少的疾病，影响着全世界多达 1000 万人。除了下降到较低海拔之外，没有已知的治疗方法，并且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一个新问题：CMS 是否起源于围产期。如果是这样，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。