Endothelin receptors modulate cardiorespiratory function during hypoxia

 描述（由申请人提供）：在我们最近努力了解人类受试者适应高海拔缺氧的基础中，我们分析了居住在高海拔（海拔> 3,500米）的蒙古人的全基因组的遗传变异。埃塞俄比亚山区的人们很好地适应了高海拔，不会像安第斯山脉的人们那样患上慢性高山病。使用选择的交叉种群测试，我们确定了在Bronchians中具有显著多样性损失的基因组区域，这表明选择性扫描。事实上，我们在几条染色体上发现了许多这样的DNA区域，其中嵌入了特定的基因。为了阐明这些基因在缺氧反应和耐受性中的潜在作用，我们在果蝇或小鼠中实验测试了这些基因是否参与缺氧，从而为它们在人类缺氧中的作用提供了额外的证据。13号染色体上的这些DNA选择区域之一含有基因内皮素受体B（EDNRB）。在哺乳动物中，这种基因编码内皮素配体的受体，内皮素配体是一种有效的血管活性肽，可以激活促进血管收缩的信号级联。由于a）有文献表明抑制内皮素受体有利于高原低氧适应，特别是关于肺动脉高压和B）EDNRB主要存在于心血管系统（CV），因此我们将重点研究EDNRB及其下调对CV系统和对低氧的细胞和分子急性反应的影响。为了实现这一目标，我们在小鼠中建立了EDNRB敲低（EDNRB+/-），以研究这种特定基因在急性缺氧中CV系统中的作用。我们的总体假设是，EDNRB在急性缺氧应激中起着重要的保护作用。具体目的1：研究EDNRB+/-中的心血管（CV）功能，并证明与野生型小鼠相比，EDNRB下调或抑制在急性缺氧中保留CV功能。具体目标2：剖析EDNRB+/-小鼠急性缺氧期间CV功能保护的基本分子机制。

 DESCRIPTION (provided by applicant): In our recent effort to understand the basis for adaptation to high altitude hypoxia in human subjects, we analyzed the whole genome of Ethiopians residing at high altitude (>3,500m above sea level) for genetic variation. Humans on the Ethiopian mountains are well adapted to high altitude and do not suffer from Chronic Mountain Sickness such as those in the Andes. Using cross-population tests of selection, we identified genomic regions with significant loss of diversity in the Ethiopians, indicative of selective sweeps. Indeed, we discovered a number of such DNA regions on several chromosomes with specific genes embedded in them. In order to elucidate the potential role of these genes in hypoxia response and tolerance, we experimentally tested whether these genes were involved in hypoxia, in either Drosophila melanogaster or mice, thus providing additional evidence for their role in hypoxia in humans. One of these DNA selected regions on chromosome 13 harbored the gene Endothelin Receptor B (EDNRB). In mammals, this gene encodes for a receptor for an endothelin ligand, a potent vasoactive peptide that activates a signaling cascade that promotes blood vessel constriction. Since a) there is literature showing that inhibition of endothelin receptors is beneficial for adaptation to high altitude hypoxia, especially regarding pulmonary hypertension and b) EDNRB is present mostly in the cardiovascular system (CV), we focus this proposal on the study of EDNRB and the effects of its down-regulation on the CV system and on the cellular and molecular acute responses to hypoxia. Towards this goal, we have created an EDNRB knock-down in mice (EDNRB+/-) to study the role of this particular gene in the CV system in acute hypoxia. Our overall hypothesis is that EDNRB plays an important protective role in acute hypoxic stress. This hypothesis will be addressed in the experiments of the following Specific Aims: Specific Aim 1: Study the cardiovascular (CV) function in EDNRB+/- and demonstrate that EDNRB down-regulation or inhibition preserves CV function in acute hypoxia as compared to wild type mice. Specific Aim 2: Dissect the molecular mechanisms that are fundamental to the preservation of the CV function during acute hypoxia in EDNRB+/- mice.