Genetic determinants of variation in the hypoxic ventilatory response in low- and high-altitude populations

低海拔和高海拔人群缺氧通气反应变异的遗传决定因素

• 批准号: 9345346
• 负责人: Erica Heinrich
• 金额: $ 5.67万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9345346
• 关键词: Acute; Age; Altitude; Andean; Asians; Basic Science; Bioinformatics; Biology; California; Candidate Disease Gene; Chronic; Chronic Obstructive Airway Disease; Comparative Study; Data; Data Set; Databases; Development; Disease Progression; Dyspnea; Elements; Environmental air flow; Epigenetic Process; Ethiopian; Ethnic Origin; Ethnic group; European; Female; Future; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Determinism; Genetic screening method; Genome; Genomics; Genotype; Goals; Hemoglobin concentration result; Hypoxia; Individual; Knowledge; Link; Literature; Lung; Lung diseases; Measurement; Measures; Mentors; Oxygen; Patients; Pattern; Phase; Phenotype; Physiological; Play; Population; Population Study; RNA; Research; Research Personnel; Research Project Grants; Role; Sampling; Sea; Signal Pathway; Sleep Apnea Syndromes; Testing; Training; Training Programs; Variant; base; biomedical scientist; career; clinical practice; gene function; genetic variant; genomic data; genotyped patients; improved; individualized medicine; male; multidisciplinary; personalized care; post-doctoral training; prevent; programs; public health relevance; reconstruction; respiratory; response; skills; trait; transcriptome; transcriptome sequencing

 DESCRIPTION (provided by applicant): The goal of this project is to identify genetic contributors to respiratory control and hypoxia tolerance. The hypoxic ventilatory response (HVR) is first line of defense when oxygen availability is reduced. The ability to sense hypoxia and increase ventilation is important for patients with respiratory diseases (e. g. sleep apnea, COPD), as well as in healthy individuals during ascent to high altitude. This project aims to (1) test the hypothesis that HVR variation is greater in ancestral highland populations compared to lowland populations, (2) test the hypothesis that an individual's HVR is explained by genetic factors related to hypoxia tolerance, and (3) to determine the role that gene expression plays in the acute response to hypoxia. Since the HVR is a key element in preventing respiratory disturbance in hypoxia, the results from this study will determine if disease progression can be predicted based on patient ancestral background. Therefore, this study will contribute to the development of individualized care and predictive strategies for pulmonary disease patients. Furthermore, this study will link genotypes to phenotypes by determining if the HVR is a function of patient genotype. These aims will be met by measuring the HVR and analyzing the expression of hypoxia-related candidate genes (e.g. EPAS-1, EGLN, HMOX2) in populations of highland and lowland ancestry. Native highlanders (Tibetans) demonstrate increased HVR variability as well as positive selection on these candidate genes compared to native lowland populations and therefore provide a valuable means for examining the relationship between genotype and the phenotypic hypoxia response. This research project is part of a postdoctoral training program in which the fellow will develop the skills necessary to launch a career as an independent biomedical scientist who will transform our understanding of lung disease and respiratory biology. The fellow will be supported by a network of pulmonary physiologist at UCSD and will focus on transforming basic science discoveries in to clinical practices.

 描述（由申请人提供）：本项目的目标是确定呼吸控制和耐缺氧的遗传因素。当氧气可用性降低时，缺氧性反应（HVR）是第一道防线。感觉缺氧和增加通气的能力对呼吸系统疾病患者很重要（例如，G.睡眠呼吸暂停，COPD），以及健康个体在上升到高海拔期间。本项目的目的是（1）测试的假设，即HVR的变化是更大的祖先高地人口相比，低地人口，（2）测试的假设，一个人的HVR是由遗传因素相关的缺氧耐受性解释，（3）以确定基因表达在急性缺氧反应中发挥的作用。由于HVR是预防缺氧呼吸障碍的关键因素，因此本研究的结果将确定是否可以根据患者的祖先背景预测疾病进展。因此，本研究将有助于制定针对肺部疾病患者的个体化护理和预测策略。此外，这项研究将通过确定HVR是否是患者基因型的函数来将基因型与表型联系起来。通过测量高原和低地血统人群的HVR和分析缺氧相关候选基因（例如EPAS-1、EGLN、HMOX 2）的表达，将满足这些目标。与本地低地人群相比，本地高原人（藏族）表现出增加的HVR变异性以及对这些候选基因的正选择，因此为研究基因型和表型缺氧反应之间的关系提供了有价值的手段。该研究项目是博士后培训计划的一部分，该研究员将发展必要的技能，以启动作为独立生物医学科学家的职业生涯，这将改变我们对肺部疾病和呼吸生物学的理解。该研究员将得到UCSD肺生理学家网络的支持，并将专注于将基础科学发现转化为临床实践。