High Altitude Adaptation: A Model for Chronic Hypoxia
高海拔适应:慢性缺氧模型
基本信息
- 批准号:8606645
- 负责人:
- 金额:$ 22万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-03-01 至 2016-02-29
- 项目状态:已结题
- 来源:
- 关键词:AcuteAdverse effectsAerobicAllelesAltitudeAttenuatedBiological AssayCatalytic DomainCell CountCell Culture TechniquesCerebrovascular DisordersChronicChronic Obstructive Airway DiseaseDNADiseaseErythrocytesErythrocytosesFunctional RNAGene ProteinsGene TargetingGenesGeneticGenomicsHaplotypesHematocrit procedureHomeostasisHydroxylationHypertensionHypoxiaHypoxia Inducible FactorHypoxia-Inducible Factor PathwayIn VitroKnowledgeLifeLungMediatingMetabolismModelingMusMutationMyocardial IschemiaOxygenPathway interactionsPatientsPhasePhenotypePhysiologicalPopulationPopulation StudyProcollagen-Proline DioxygenaseProtein IsoformsProteinsPulmonary HypertensionRegulationReporter GenesSamplingSeaSeriesSingle Nucleotide PolymorphismTherapeuticTranslatingbHLH-PAS factor HLFbasegain of functiongenetic variantgenome wide association studyhypoxia inducible factor 1in vitro Assayloss of functionmeternovel therapeutic interventionprotein protein interactionpublic health relevancerespiratoryresponsescreeningsensortranscription factor
项目摘要
DESCRIPTION (provided by applicant): Chronic hypoxia is a central feature of many diseases, including ischemic heart disease, cerebrovascular disease, and chronic obstructive pulmonary disease. Understanding the cellular and physiologic responses to chronic hypoxia will provide the basis for therapies for these widely prevalent diseases. The central transcriptional response to hypoxia is mediated by the Prolyl Hydroxylase Domain (PHD):Hypoxia Inducible Factor (HIF) pathway. In this pathway, PHD (which consists of three isoforms) prolyl hydroxylates the ? subunit of HIF (which consists of three isoforms) and targets the latter for degradation. Under hypoxia, PHD activity is attenuated, allowing for the stabilization of HIF-? and the activation of a broad range of genes involved in hypoxic adaptation, such as ones that promote a shift from aerobic to anaerobic metabolism. One might presume that activation of this pathway would be of direct benefit in these diseases. However, it is clear that chronic activation of this pathway leads to two potentially serious adverse effects, pulmonary hypertension and erythrocytosis. Therapeutic manipulation of this pathway mandates identifying means of tempering these adverse effects. Study of the Tibetan population, who have adapted to high altitudes and chronic hypoxia, offers a unique opportunity to pursue this. Strikingly, this population has avoided the pulmonary hypertension and erythrocytosis that afflict low altitude dwellers who ascend to high altitudes. Hence, if one were able to identify the mechanisms by which this occurs, this would allow approaches that could ameliorate these consequences. A large number of independent genome wide studies of the Tibetan population have recently provided convincing evidence for a genetic basis for this adaptation, and they consistently point to two genes, the PHD2 (also known as EGLN1) and HIF2A (also known as EPAS1) genes. In this application, we will focus on the PHD2 gene. The above referenced studies have identified a series of intronic and exonic single nucleotide polymorphisms (SNPs) that are enriched in the Tibetan population. In the initial R21 phase of the proposed project, we will first identify the functionally important SNP through a series of in vitro assays that will include reporter gene, protein:protein interaction, and cell culture-based assays. In the subsequent R33 phase of the proposed project, we will generate a mouse knockin line to model the Tibetan SNP. We will then examine the capacity of this SNP to ameliorate the pulmonary hypertension and erythrocytosis that is seen in two independent models of chronic hypoxia. In one model, we will expose these mice to hypoxia for three weeks. In the second model, we will cross these mice with a recently generated mouse line bearing a knockin Hif2a mutation that displays highly penetrant erythrocytosis and pulmonary hypertension. We anticipate that the proposed studies will identify a pathway by which the hypoxic response can be engaged while minimizing its most serious adverse effects.
描述(由申请人提供):慢性缺氧是许多疾病的核心特征,包括缺血性心脏病,脑血管疾病和慢性阻塞性肺部疾病。了解对慢性缺氧的细胞和生理反应将为这些广泛普遍的疾病提供疗法的基础。对缺氧的中心转录反应是由羟基羟化酶结构域(PHD)介导的:缺氧诱导因子(HIF)途径。在此途径中,博士学位(由三个同工型组成)丙酰羟基盐酸盐? HIF的亚基(由三种同工型组成),并靶向后者降解。在缺氧下,PHD活性减弱,允许HIF-稳定?以及参与低氧适应的广泛基因的激活,例如促进从有氧运动转向厌氧代谢的基因。人们可能会认为,在这些疾病中,这种途径的激活将是直接的好处。但是,很明显,该途径的慢性激活会导致两种潜在的严重不良反应,肺动脉高压和红细胞增多症。对该途径的治疗操纵要求识别缓解这些不良反应的手段。 对藏族人口的研究,他们适应了高海拔高度和慢性缺氧,为追求这一点提供了独特的机会。令人惊讶的是,该人群避免了肺动脉高压和红细胞增多症,使高海拔高度的低海拔居民。因此,如果一个人能够确定发生这种情况的机制,这将允许可以改善这些后果的方法。藏族人口的大量独立基因组广泛的研究最近为这种适应提供了令人信服的证据,它们始终指向两个基因PHD2(也称为EGLN1)和HIF2A(也称为EPAS1)基因。在此应用中,我们将重点关注PHD2基因。上述参考研究确定了一系列富含藏族人群的内含子和外显子核苷酸多态性(SNP)。在拟议项目的最初R21阶段中,我们将通过一系列体外测定法识别出功能上重要的SNP,其中包括报告基因,蛋白质:蛋白质相互作用和基于细胞培养的测定法。在拟议项目的随后的R33阶段中,我们将生成一条小鼠敲击线来对藏族SNP进行建模。然后,我们将检查该SNP的能力来改善肺动脉高压和红细胞增多症,这在两个独立的慢性缺氧模型中可以看到。在一个模型中,我们将把这些小鼠暴露于缺氧三周。在第二个模型中,我们将用最近生成的小鼠系穿过这些小鼠,该小鼠系带有敲击蛋白HIF2A突变,该突变显示高度渗透性红细胞增多和肺动脉高压。我们预计拟议的研究将确定可以参与低氧反应的途径,同时最大程度地减少其最严重的不良反应。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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FRANK S LEE其他文献
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{{ truncateString('FRANK S LEE', 18)}}的其他基金
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9027529 - 财政年份:2015
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