Molecular Basis of Hypoxia-Induced Excessive Erythrocytosis

项目摘要/摘要 高达20%的人生活在秘鲁山区的高海拔地区，更少的人 在西藏获得学位，患有蒙格病或慢性高原病(CMS)。这些受试者死得很早 成年后因红细胞增多症(红细胞增多症、红细胞压积和GT；60%)。据估计，有 世界上有超过1亿人生活在海拔2500米的地方，他们面临着CMS的风险。我们特别是 对CMS患者感兴趣是因为他们构成了一个独特的群体，使我们能够研究 基于环境条件，红血球生成的机制可能会变得错误或被夸大。这个 当我们意识到有一些人生活在一起时，这个群体的独特性就更加重要了 一侧与CMS患者的海拔相似，但没有患上这种疾病。 我们已经通过全基因组测序证明，有几个全基因组 秘鲁受试者中与选择性扫描一致的区域(包含多个基因) 红细胞增多症。此外，通过使用来自CMS和非CMS受试者的皮肤活检和自然血细胞， 我们已经获得了iPS细胞，并将它们分化为红细胞。我们将在此应用程序中使用 我们已经分析了&gt；100 CMS和非CMS以及其他受试者的全基因组结果 分子和基因组工具，以更好地了解SENP1在缺氧中的作用，并了解 女性保护的机制基础。根据我们的初步结果，我们制定了中央 高原低氧性红细胞增多症有遗传基础和SENP1的假说 在蒙格氏病中红细胞增多症的这一极端特征中起着关键作用。我们的具体目标是： 具体目标1：阐明SENP1单核苷酸多态(SNPs)在 CMS中显著的缺氧性红细胞增多症的调控及非CMS中的缺失 研究对象。我们假设特定的SNPs在CMS中调节SENP1的上调，而在非CMS中不调节 对缺氧的反应。 具体目标2：确定发挥重要作用的转录变化和途径 在CMS的缺氧性红细胞增多症中。我们假设SENP1的上调将导致 CMS细胞中导致CMS多核细胞表型的特异转录变化。 具体目标3：探讨激素因素在性别依赖性高海拔地区的作用 诱导过多的红细胞生成。我们假设雌激素对SENP1/GATA1的影响是 负责保护女性免受CMS红细胞增多症的影响。

Project Summary/Abstract Up to twenty percent of individuals living at high altitude in the Peruvian mountains and, to a lesser degree in Tibet, suffer from Monge's disease or Chronic Mountain Sickness (CMS). These subjects die in early adulthood because of excessive erythrocytosis (Polycythemia, hematocrit>60%). It is estimated that there are over 100 million people who live at altitudes > 2500 m world-wide, who are at risk for CMS. We are particularly interested in patients with CMS because they constitute a unique population that allows us to study how mechanisms of erythropoiesis can become awry or get exaggerated based on environmental conditions. The uniqueness of this population is even more significant when we realize that there are subjects that live side by side at similar altitudes as those with CMS but do not suffer from this disease. We have already demonstrated through whole genome sequencing that there are several genome-wide regions (containing a number of genes) that are consistent with selective sweeps in Peruvian subjects with polycythemia. Further, with the use of skin biopsies and native blood cells from CMS and non-CMS subjects, we have obtained iPS cells and differentiated them into red blood cells. We will use in this application the results of our already analyzed whole genomes of >100 CMS and non-CMS subjects as well as other molecular and genomic tools to better understand the role of SENP1 in hypoxia and understand the mechanistic basis of protection in females. Based on our preliminary results, we have formulated the central hypothesis that the hypoxia-induced polycythemia of high altitude has a genetic basis and that SENP1 plays a critical role in this extreme trait of polycythemia in Monge's disease. Our Specific Aims are: Specific Aim 1: Elucidate the role of SENP1 single nucleotide polymorphisms (SNPs) in regulating the marked hypoxia-induced polycythemia in CMS and the lack thereof in non-CMS subjects. We hypothesize that specific SNPs regulate SENP1 up-regulation in CMS but not in non-CMS in response to hypoxia. Specific Aim 2: Determine the transcriptomic changes and pathways that play an important role in the hypoxia-induced polycythemia in CMS. We hypothesize that an up-regulation of SENP1 will induce specific transcriptional changes in CMS cells that lead to the CMS polycythemic phenotype. Specific Aim 3: Investigate the role of hormonal factors in the gender-dependent high altitude induced excessive erythropoiesis. We hypothesize that the effect of estrogen hormone on SENP1/GATA1 is responsible for protection of females from CMS polycythemia.