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：
9229060
负责人：
FRANK S LEE
金额：
$ 49.68万
依托单位：
UNIVERSITY OF PENNSYLVANIA
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 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9229060
关键词：
Acute Adverse effects Aerobic Alleles Altitude Anaerobic Bacteria Attenuated Biological Assay Catalytic Domain Cell Count Cell Culture Techniques Cerebrovascular Disorders Chronic Chronic Obstructive Airway Disease DNA Disease Erythrocytes Gene Targeting Genes Genetic Genetic Transcription Genomics Haplotypes Hematocrit procedure Homeostasis Hydroxylation Hypertension Hypoxia Hypoxia Inducible Factor Hypoxia-Inducible Factor Pathway Impairment In Vitro Knock-in Knock-in Mouse Knowledge Lung Mediating Metabolism Modeling Mus Mutation Myocardial Ischemia Oxygen Pathway interactions Patients Phase Phenotype Physiological Population Procollagen-Proline Dioxygenase Protein Isoforms Proteins Pulmonary Hypertension Reporter Genes Sampling Sea Series Single Nucleotide Polymorphism Therapeutic Translating Untranslated RNA base gain of function genetic signature genetic variant genome-wide analysis in vitro Assay loss of function meter novel therapeutic intervention protein protein interaction public health relevance respiratory response screening sensor study population transcription 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 α 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-α 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（由申请人证明）：慢性缺氧是冬季疾病，并察觉到慢性缺氧Willapi是ES的基础。 y。参与缺氧的基因，例如促进有氧运动的转变。效果。，它们始终指向两个基因，即PHD2（也称为EGLN1）和HIF2A（也称为EPAS1），我们将重点介绍上述参考研究。 SNP富含藏族人，我们将通过一系列重要的体外测定法，其中包括报告基因，Protetein：蛋白质相互作用和基于培养的测定法。藏族snp的支撑项目将使该SNP的cap缩在一个模型中，我们将在一个模型中暴露于一个模型中。产生的小鼠系带有敲击蛋白HIF2A突变，即高度渗透性红细胞增多症和肺动脉高压。