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: 10310983
• 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/10310983
• 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; Failure; 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; Pulmonary artery structure; 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; Ventricular; Wild Type Mouse; Work; Y Chromosome; angiogenesis; bosentan; cell type; cohort; cytokine; innovation; knock-down; lung hypoxia; macrophage; male; mouse model; new therapeutic target; pressure; protective effect; protective factors; pulmonary arterial hypertension; receptor; response; 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.

摘要 肺动脉高压是一种以肺动脉高压为特征的慢性肺部疾病， 压力导致右心室（RV）肥大、RV衰竭和死亡。PAH的发病率很高， 女性患者比例更高（4：1）。虽然以前的研究调查PAH的性别差异， 广泛研究性腺激素的作用，特别是雌激素，我们是第一个研究 PAH的性染色体我们最近发表的工作使用创新的小鼠模型， 在缺乏性激素的情况下，Y染色体（ChrY）可防止实验性肺动脉高压 (PH)ChrY上只有4个基因在大肠杆菌中表达，表明ChrY上编码的基因可以抵抗PH。 肺Uty、Kdm 5d、Eif 2s 3 y和Ddx 3 y。我们的初步数据确定Uty为最佳候选基因 此外，我们证明，在雄性中，Uty表达减少， 我们对PH野生型（WT）肺的RNAseq分析 和Uty-KD雄性小鼠揭示了一些有希望的靶点，包括促炎细胞因子Cxcl 9和 Cxcl 10.我们的初步数据显示Uty与Cxcl 9/10共定位于肺巨噬细胞中，并且Uty的表达与Cxcl 9/10的表达相关。 Cxcl 9/10在从Uty global KO小鼠分离的骨髓来源的巨噬细胞中显著增加 与WT相比。更重要的是，我们的初步研究表明，阻断共享的Cxc 19/10受体Cxcr 3， 使用AMG 487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还发现， 由于Uty-KD，内皮素-2（ET-2）在肺中上调。ET-2的作用目前尚不清楚， 多环芳烃。我们首次发现，ET-2表达增加可能通过抑制肺动脉高压而导致肺动脉高压恶化。 血管生成和促进肺中SMC增殖。我们的工作假设是：（1）ChrY基因Uty 防止PH的发展;（2）Uty的缺失或缺失通过增加 Cxcl 9/10和ET-2的表达导致血管EC死亡、SMC增殖和病理学改变。 单独阻断Cxcl 9/10或与阻断ET-2活性一起阻断Cxcl 9/10可降低PH的严重性。 以一种特定于性别的方式。目标1。为了检查是否在肺中敲除Uty，在存在和 激素的情况下，废除ChrY在实验PH的保护作用;目的2。探讨 Uty/Cxcl 9/10和Uty/ET-2轴在PH发病机制中的机制作用;目的3.确定是否阻止 下游Uty基因Cxcl 9/10的活性单独或与阻断ET-2一起通过以下方式挽救PH发展： 减少EC凋亡和SMC增殖，促进血管新生。