Perinatal Origins of Chronic Mountain Sickness

慢性高山病的围产期起源

基本信息

批准号：
8048104
负责人：
LORNA G. MOORE
金额：
$ 3.75万
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/8048104
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 Health Heart failure Hemoglobin Hemoglobin concentration result High birth weight infant Hypoxia Individual Intervention Interview Laboratories Life Linear Regressions Logistic Regressions 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 regulatory protein genetic variant hypoxia neonatorum interest lung maturation male meetings men mortality novel parent grant pre-clinical prevent promoter 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.

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.在怀孕期间提出了一系列研究，在100个高（3600 m）和100个低位（300 m）高度居民中，提出了序列研究，分别在多代高海拔（安第斯）或低空（欧洲）血统的妇女之间。 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在母体生理反应中，安第斯与欧洲人的怀孕。在此FIRCA中，我们建议扩展研究，以检验以下假设：低氧环境中的妊娠和出生会导致对呼吸和肺结构的控制终生改变，因此功能性改变，增加了成年后对慢性山地疾病（CMS）的易感性。我们的具体目的将胎儿起源假设扩展到肺循环和/或呼吸控制的异常，是1）表征1）表征血红蛋白水平升高或过度红细胞化的年轻人的表型，或者在a循环和睡眠循环中的呼吸和呼吸器的早期形式（EE），均为呼吸和睡眠，B）氧化还原状态和2）确定EE在围产期生命期间EE是否更缺氧，通过将他们与一组健康对照组进行比较，就他们经历的患病率a）胎儿生长降低，b）先兆子痫，c）新生儿缺氧。我们和其他人最近的工作支持了EE具有围产期起源的拟议假设。拟议的研究将确定高海拔高度（E3600M）的150名男性（15-25岁）居民； 75具有EE和75个健康对照。将受试者按年龄和居住高度匹配，将在睡眠和清醒，肺结构和功能，肺循环，氧化还原状态和血液学特征的情况下进行比较。将进行访谈和医学纪录评论，以评估围产期期间慢性缺氧之间的关系，或成年后的胎儿生长和EE减少。这些母体和围产期特征，通气功能，肺结构和肺循环异常，成年后的氧化还原状态和EE之间的关系将使用一系列的后勤和线性回归分析来确定。了解CMS的起源将有助于早期认可和预防这一公共卫生问题，该公共卫生问题影响了约10％的成年男性，或全球1000万人，构成了南美，亚洲和美国高地地区发病率和死亡率的主要原因。绩效网站（S）（组织，城市，州）拉巴斯，玻利维亚关键人员：科罗拉多州科罗拉多大学丹佛大学丹佛大学博士大学玻利维亚诺（Boliviano de Biologma de Altura de Altura de Altura共同投资者Susan Niermeyer），医学博士丹佛大学丹佛大学顾问Teofilo Lee-Chiong，医学博士国家犹太医学和研究中心研究中心顾问约翰·基特尔森（John Kittelson），博士全球。除了下降到较低的高度外，它没有已知的补救措施，并且可能导致肺动脉高压和正确的心力衰竭死亡。我们提出的研究提出了一个新的问题，即CMS是否具有围产期起源。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。