Role of Chromosome Y gene, Uty, in protecting against Pulmonary Hypertension

Y 染色体基因 Uty 在预防肺动脉高压中的作用

• 批准号: 10454301
• 负责人: Mansoureh Eghbali
• 金额: $ 47.31万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-20 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10454301
• 关键词: Alveolar Macrophages; Animal Model; Apoptosis; Attenuated; Bioinformatics; Bone Marrow; CXCL9 gene; Candidate Disease Gene; Cell Death; Cell Proliferation; Cells; Cessation of life; Chronic lung disease; Collaborations; Data; Data Set; Development; Endothelial Cells; Endothelin Receptor Antagonist; Endothelin-1; Endothelin-2; Endothelium; Estrogens; Female; Functional disorder; Genes; Gonadal Hormones; Gonadal Steroid Hormones; Health; Hormones; Human; Incidence; Knockout Mice; Lung; Mus; Pathogenesis; Pathologic Neovascularization; Patients; Pilot Projects; Publishing; Pulmonary Hypertension; Rattus; Recombinants; Right Ventricular Hypertrophy; Role; Sampling; Severities; Sex Chromosomes; Sex Differences; Smooth Muscle Myocytes; Testing; Therapeutic Uses; Time; Transgenic Organisms; Up-Regulation; Vascular Endothelial Cell; Wild Type Mouse; Work; Y Chromosome; angiogenesis; antagonist; bosentan; cell type; cohort; cytokine; innovation; knock-down; lung hypoxia; macrophage; male; mouse model; new therapeutic target; protective effect; protective factors; pulmonary arterial hypertension; pulmonary arterial pressure; receptor; response; right ventricular failure; sex; transcriptome sequencing; vascular smooth muscle cell proliferation

ABSTRACT Pulmonary arterial hypertension (PAH) is a chronic lung disease characterized by increased pulmonary artery pressure leading to right ventricular (RV) hypertrophy, RV failure and death. The incidence of PAH is much higher in female patients (4:1 ratio). While previous studies investigating sex differences in PAH have focused extensively on the role of gonadal hormones, in particular estrogen, we are the first lab to investigate the role of sex chromosomes in PAH. Our recent published work using innovative mouse models demonstrated in the absence of sex hormones, the Y chromosome (ChrY) protects against experimental pulmonary hypertension (PH), indicating that gene(s) encoded on ChrY can protect against PH. Only 4 genes on ChrY are expressed in the lungs Uty, Kdm5d, Eif2s3y, and Ddx3y. Our preliminary data identified Uty as the top candidate gene responsible for ChrY protection against PH. Additionally, we demonstrate that Uty expression is reduced in male patients with PAH and multiple animal models of PH. Our RNAseq analysis on the lungs of PH wildtype (WT) and Uty-KD male mice revealed a few promising targets including the proinflammatory cytokines Cxcl9 and Cxcl10. Our preliminary data shows Uty co-localizes with Cxcl9/10 in lung macrophages, and expression of Cxcl9/10 is significantly increased in bone marrow derived macrophages isolated from Uty global KO mice compared to WT. More importantly, our pilot study shows that blocking the shared Cxcl9/10 receptor, Cxcr3, using AMG487 can reduce PH severity in female rats with PH. Our bioinformatics analysis also identified Endothelin-2 (ET-2) is up-regulated in the lung as a result of Uty-KD. The role of ET-2 is currently unknown in PAH. For the first time, we show that increased ET-2 expression may contribute to worsening PH by inhibiting angiogenesis and promoting SMC proliferation in the lung. Our working hypotheses are: (1) ChrY gene Uty protects against PH development; (2) loss or absence of Uty results in more severe PH through increased expression of Cxcl9/10 and ET-2 resulting in vascular EC death, SMC proliferation and pathological angiogenesis; and (3) Blocking Cxcl9/10 alone or together with blocking ET-2 activity reduces the severity of PH in a sex-specific manner. Aim 1. To examine whether knockdown of Uty in the lungs, in the presence and absence of hormones, abolishes the protective role of ChrY in experimental PH; Aim 2. Investigate the mechanistic role of the Uty/Cxcl9/10 and Uty/ET-2 axes in PH pathogenesis; Aim 3. Determine if blocking the activity of downstream Uty genes Cxcl9/10 alone or together with blocking ET-2 rescues PH development by reducing EC apoptosis and SMC proliferation and promoting angiogenesis in male and female rats.

抽象的 肺动脉高压（PAH）是一种慢性肺部疾病，其特征是肺动脉增加 导致右心（RV）肥大，RV衰竭和死亡的压力。 PAH的发生率很多 女性患者较高（4：1）。虽然先前研究PAH性别差异的研究集中在 关于性腺激素的作用，特别是雌激素，我们是第一个研究的实验室 PAH中的性染色体。我们最近发表的使用创新的鼠标模型在 缺乏性激素，Y染色体（CHRY）可预防实验性肺动脉高压 （pH），表明在Chry上编码的基因可以预防pH。 Chry上只有4个基因在 肺UTY，KDM5D，EIF2S3Y和DDX3Y。我们的初步数据将UTY确定为顶级候选基因 负责保护pH的chry保护。此外，我们证明了雄性的UTY表达降低 患有PAH的患者和多种pH动物模型。我们对pH WildType肺（WT）肺的RNASEQ分析 和UTY-KD雄性小鼠揭示了一些有希望的靶标，包括促炎细胞因子CXCL9和 CXCL10。我们的初步数据显示了肺巨噬细胞中与CXCL9/10的UTY共定位，并表达 从UTY Global KO小鼠分离的骨髓衍生的巨噬细胞中，CXCL9/10显着增加 与wt相比。更重要的是，我们的试点研究表明，阻止共享的CXCL9/10受体CXCR3， 使用AMG487可以降低pH雌性大鼠的pH严重程度。我们的生物信息学分析也确定了 由于UTY-KD，内皮素-2（ET-2）在肺中被上调。 ET-2的作用目前未知 pah。我们首次表明，ET-2表达的增加可能会通过抑制来导致pH恶化 血管生成并促进肺中的SMC增殖。我们的工作假设是：（1）Chry Gene uty 防止pH发育； （2）损失或缺乏通过增加而导致更严重的pH CXCL9/10和ET-2的表达导致血管EC死亡，SMC增殖和病理学 血管生成； （3）单独阻断CXCL9/10或与阻断ET-2活性一起降低pH的严重程度 以特定的方式。目的1。检查是否在肺中敲击uty，在场和 缺乏激素，废除了Chry在实验pH中的保护作用。目标2。调查 UTY/CXCL9/10和UTY/ET-2轴在pH发病机理中的机械作用；目标3。确定是否阻止 下游UTY基因CXCL9/10的活性单独或与阻塞ET-2一起挽救了pH的发育 减少EC凋亡和SMC增殖并促进雄性和雌性大鼠的血管生成。