Molecular Basis of Hypoxia-Induced Excessive Erythrocytosis

缺氧引起红细胞增多症的分子基础

• 批准号: 10443584
• 负责人: Gabriel G Haddad
• 金额: $ 59.11万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-05 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10443584
• 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; Persons; 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

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.

项目总结/摘要 多达20%的人生活在秘鲁山区的高海拔地区， 在西藏，患有蒙氏病或慢性高山病（CMS）。这些实验对象死得早 成年期红细胞过多（红细胞增多症，红细胞压积> 60%）。估计有 全世界有超过1亿人生活在海拔2500米以上的地区，他们面临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人群，使我们能够研究如何 红细胞生成的机制可能基于环境条件而变得错误或被夸大。的 当我们意识到有一些主题生活在一起时，这个群体的独特性就更加重要了。 与CMS患者处于相似的海拔高度，但不患有这种疾病。 我们已经通过全基因组测序证明，有几个基因组范围的 区域（包含一些基因），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受试者的皮肤活组织检查和天然血细胞， 我们已经获得了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> 100个CMS和非CMS受试者以及其他受试者的全基因组的结果。 分子和基因组工具，以更好地了解SENP 1在缺氧中的作用，并了解 保护女性的机械基础。根据我们的初步结果，我们制定了中央 高原缺氧性红细胞增多症有遗传基础，SENP 1 在这种极端的红细胞增多症中起着关键作用。我们的具体目标是： 具体目标1：阐明SENP 1单核苷酸多态性（SNP）在 调节CMS中显著的缺氧诱导的红细胞增多症和非CMS中的缺乏 科目我们假设特定的SNPs在CMS中调节SENP 1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组学变化和途径 缺氧诱导的CMS红细胞增多症。我们假设SENP 1的上调将诱导 CMS细胞中导致CMS红细胞增多表型的特异性转录变化。 具体目标3：探讨激素因素在性别依赖性高海拔中的作用 导致红细胞生成过多。我们推测雌激素对SENP1/GATA 1的作用是通过调节SENP1/GATA 1的表达来实现的。 负责保护女性免受CMS红细胞增多症。

项目成果

Long noncoding RNA HIKER regulates erythropoiesis in Monge's disease via CSNK2B.

• DOI: 10.1172/jci165831
• 发表时间: 2023-06-01
• 期刊: JOURNAL OF CLINICAL INVESTIGATION
• 影响因子: 15.9
• 作者: Azad, Priti;Zhou, Dan;Tu, Hung-Chi;Villafuerte, Francisco C.;Traver, David;Rana, Tariq M.;Haddad, Gabriel G.
• 通讯作者: Haddad, Gabriel G.

Genetic and molecular basis of Adaptive and Mal-adaptive excessive erythropoietic responses in the Andean region.

安第斯地区适应性和适应性不良过度红细胞生成反应的遗传和分子基础。

• 发表时间: 2022
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: Azad,Priti;Zhou,Dan;Haddad,Gabriel
• 通讯作者: Haddad,Gabriel

Protective role of estrogen against excessive erythrocytosis in Monge's disease.

• DOI: 10.1038/s12276-020-00550-2
• 发表时间: 2021-01
• 期刊: Experimental & molecular medicine
• 影响因子: 12.8
• 作者: Azad P;Villafuerte FC;Bermudez D;Patel G;Haddad GG
• 通讯作者: Haddad GG