Respiratory and genomic contributions to adaptive/maladaptive hypoxia responses

呼吸和基因组对适应性/适应不良缺氧反应的贡献

基本信息

批准号：
10642768
负责人：
Tatum S Simonson
金额：
$ 47.62万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-10 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10642768
关键词：
Accounting Admixture Age Altitude Altitude Sickness Andean Animals Biological Markers Cardiopulmonary Cardiovascular system Cell Line Chronic Data Disease Epigenetic Process Erythrocytoses European Exhibits Female Gene Expression Generations Genes Genetic Genetic Determinism Genomics Genotype Heart Diseases Hemoglobin Homeostasis Human Hypercapnia Hypertension Hypoxemia Hypoxia Hypoxia-Inducible Factor Pathway Individual Individual Differences Lung diseases Malignant Neoplasms Measures Menstrual cycle Modification Native American Ancestry Natural Selections Outcome Oxygen Pathway interactions Patients Phenotype Physiological Population Prevention Pulmonary Heart Disease Reflex action Rest Role Scanning Sea Severities Sleep Sleep Apnea Syndromes Stress Stroke Testing Therapeutic Variant Woman epigenetic regulation exercise capacity genetic predictors genetic variant genomic locus human disease insight loss of function male men novel oxygen transport respiratory response trait ventilation whole genome

项目摘要

Project Summary/Abstract The ability to use oxygen effectively is essential for survival. Many significant human diseases, including cardiopulmonary disease, hypertension, sleep apnea, and cancer involve a disruption in oxygen homeostasis. Human populations at high altitude have been challenged by hypoxia for hundreds of generations and show both unique physiological responses to this environmental stress and extremely strong natural selection for genes involved in oxygen transport, which can be demonstrated in relatively small studies. For example, we were the first to demonstrate a relationship between genes in the hypoxia inducible factor (HIF) pathway under natural selection and relatively lower hemoglobin concentration, which is further associated with exercise capacity, in Tibetans. Here we propose a similar integrative and targeted approach to identify the genetic determinants of both adaptive and maladaptive cardiopulmonary responses to hypoxia in Andean natives, who show a wide range of cardiorespiratory phenotypes, including chronic mountain sickness (CMS) rare among Tibetans. CMS is characterized by excessive erythrocytosis, arterial hypoxemia, carbon dioxide retention, and blunted ventilatory chemoreflexes, which are also traits associated with poor outcomes in patients with chronic heart and lung disease. We propose to test the overarching hypothesis that individual differences in cardiopulmonary phenotypes (hemoglobin concentration, arterial oxygen saturation, hypoxic/hypercapnic ventilatory and cardiovascular responses) are predicted by (1) a lack of adaptive variants and/or (2) altered epigenetic regulation at loci identified with powerful state-of-the-art genomic analyses of Andean men and women with and without CMS. We will also test the hypothesis that the severity of sleep apnea underlies epigenetic changes that further modify cardiopulmonary responses as previously demonstrated in animal studies of intermittent hypoxia. Finally, we will determine if genetic and epigenetic variants result in gain- or loss-of-function to pursue therapeutic options for mitigating maladaptive responses to hypoxia in patients at sea level with chronic heart and lung disease.

项目概要/摘要有效利用氧气的能力对于生存至关重要。许多重大的人类疾病，包括心肺疾病、高血压、睡眠呼吸暂停和癌症都涉及中断在氧稳态中。高海拔地区的人群面临着缺氧的挑战数百代人对此表现出独特的生理反应环境压力和与氧有关的基因的极强自然选择运输，这可以通过相对较小的研究来证明。例如，我们是第一个证明缺氧诱导因子 (HIF) 通路中基因之间的关系在自然选择和相对较低的血红蛋白浓度下，这进一步与藏族人的运动能力有关。在这里，我们提出了类似的综合和有针对性的方法来确定适应性和适应不良的遗传决定因素安第斯土著人对缺氧的心肺反应表现出广泛的心肺表型，包括藏族人中罕见的慢性高山病（CMS）。 CMS 的特点是红细胞过多、动脉低氧血症、二氧化碳潴留、和通气化学反射迟钝，这也是与不良结果相关的特征患有慢性心脏病和肺病的患者。我们建议检验总体假设心肺表型（血红蛋白浓度、动脉血红蛋白浓度）的个体差异预测氧饱和度、低氧/高碳酸血症通气和心血管反应）通过（1）缺乏适应性变异和/或（2）在确定的位点改变表观遗传调控对有或没有 CMS 的安第斯男性和女性进行强大的、最先进的基因组分析。我们还将检验以下假设：睡眠呼吸暂停的严重程度是表观遗传变化的基础进一步改变心肺反应，正如先前在动物研究中所证明的那样间歇性缺氧。最后，我们将确定遗传和表观遗传变异是否会导致增益- 或功能丧失以寻求减轻缺氧适应不良反应的治疗方案患有慢性心肺疾病的海平面患者。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Preserved peak exercise capacity in Andean highlanders with excessive erythrocytosis both before and after isovolumic hemodilution.

DOI：
10.1152/japplphysiol.00439.2022
发表时间：
2023-01-01
期刊：
JOURNAL OF APPLIED PHYSIOLOGY
影响因子：
3.3
作者：
Anza-Ramirez, Cecilia;Gu, Wanjun;Macarlupu, Jose L.;Figueroa-Mujica, Romulo J.;Vizcardo-Galindo, Gustavo A.;Heinrich, Erica C.;Tift, Michael S.;Wagner, Harrieth E.;Wagner, Peter D.;Simonson, Tatum S.;Villafuerte, Francisco C.
通讯作者：
Villafuerte, Francisco C.

EPAS1/HIF-2α: a key regulator for chronic hypoxia across species.