Endothelin receptors modulate cardiorespiratory function during hypoxia

 描述(申请人提供)：在我们最近努力了解人类受试者适应高海拔低氧的基础时，我们分析了居住在高海拔(海拔3500米)的埃塞俄比亚人的整个基因组的遗传变异。埃塞俄比亚山区的人类很好地适应了高海拔，不会像安第斯山脉的人那样患有慢性高山病。使用选择的跨种群测试，我们确定了埃塞俄比亚人中多样性显著丧失的基因组区域，这表明有选择性的扫描。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低氧反应和耐受中的潜在作用，我们在实验中测试了这些基因是否与低氧有关，无论是在果蝇还是小鼠身上，从而为它们在人类低氧中的作用提供了额外的证据。在13号染色体上的这些DNA选择区域中，有一个含有内皮素受体B(EDNRB)基因。在哺乳动物中，这个基因编码内皮素配体的受体，这是一种有效的血管活性多肽，可以激活促进血管收缩的信号级联反应。由于有文献表明抑制内皮素受体有助于适应高原低氧，特别是对于肺动脉高压和b)EDNRB主要存在于心血管系统(CV)，我们重点研究EDNRB及其下调对CV系统和对细胞和分子的急性缺氧反应的影响。为了实现这一目标，我们在小鼠中建立了EDNRB基因敲除(EDNRB+/-)，以研究该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在急性低氧应激中起着重要的保护作用。这一假说将在以下特定目标的实验中得到解决：特定目标1：研究EDNRB+/-的心血管功能，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了心血管功能。具体目标2：剖析在EDNRB+/-小鼠急性缺氧期间维持心血管功能的基本分子机制。

 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.