Molecular Basis of Hypoxia-Induced Excessive Erythrocytosis

缺氧引起红细胞增多症的分子基础

基本信息

批准号：
10204098
负责人：
Gabriel G Haddad
金额：
$ 59.9万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-05 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10204098
关键词：
Adult Alaska Altitude Altitude Sickness Andean Biopsy Blood Blood Cells CD34 gene CRISPR/Cas technology California Candidate Disease Gene Cell Differentiation process Cells Chronic Colorado DNA Development Disease Erythrocytes Erythropoiesis Estrogens Female Fibroblasts Frequencies GATA1 gene Gender Gene Expression Genes Genetic Genetic Polymorphism Genetic Transcription Genome Gonadal Steroid Hormones Haplotypes Hematocrit procedure Hormonal Hormones Hypoxia In Vitro Individual Lead Mammals Mediating Menopause Molecular Myocardial Infarction Pathway interactions Patients Peruvian Phenotype Play Polycythemia Population Progesterone Research Risk Role Sea Sequence Analysis Sex Bias Side Single Nucleotide Polymorphism Skin Stroke System Testosterone Tibet Up-Regulation Washington base disorder risk emerging adult epidemiology study gender difference genome analysis genome sequencing genome-wide genomic tools in vivo induced pluripotent stem cell interest male new therapeutic target normoxia overexpression predictive test response trait transcriptome sequencing transcriptomics whole genome

项目摘要

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.

项目概要/摘要高达百分之二十的人生活在秘鲁山区的高海拔地区，少数人生活在高海拔地区在西藏获得学位，患有蒙日病或慢性高山病（CMS）。这些对象早逝成年后因红细胞过多（红细胞增多症，血细胞比容>60%）。估计有全球有超过 1 亿生活在海拔 > 2500 米的人面临 CMS 的风险。我们特别对 CMS 患者感兴趣，因为他们构成了一个独特的群体，使我们能够研究如何红细胞生成机制可能会因环境条件而出现偏差或夸大。这当我们意识到有一些对象毗邻居住时，这个群体的独特性就变得更加重要与患有 CMS 的人处于相似的海拔高度，但没有患这种疾病。我们已经通过全基因组测序证明，有几个全基因组范围的基因区域（包含许多基因）与秘鲁受试者的选择性扫描一致红细胞增多症。此外，通过使用来自 CMS 和非 CMS 受试者的皮肤活检和天然血细胞，我们获得了iPS细胞并将其分化为红细胞。我们将在此应用程序中使用我们已经分析了超过 100 个 CMS 和非 CMS 受试者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，我们制定了中央假设高原缺氧引起的红细胞增多症有遗传基础，SENP1 在蒙日氏病红细胞增多症的这种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 单核苷酸多态性 (SNP) 在调节 CMS 中明显缺氧诱导的红细胞增多症以及非 CMS 中红细胞增多症的缺乏科目。我们假设特定的 SNP 在 CMS 中调节 SENP1 上调，但在非 CMS 中则不然。对缺氧的反应。具体目标 2：确定发挥重要作用的转录组变化和途径 CMS 中缺氧诱导的红细胞增多症。我们假设 SENP1 的上调会诱导 CMS 细胞中导致 CMS 多细胞增多表型的特定转录变化。具体目标 3：研究激素因素在性别依赖性高海拔中的作用诱发红细胞生成过多。我们推测雌激素对SENP1/GATA1的影响是负责保护女性免受 CMS 红细胞增多症的侵害。