Novel mechanisms of obliterative pulmonary vascular remodeling and severe pulmonary arterial hypertension

闭塞性肺血管重塑和严重肺动脉高压的新机制

• 批准号: 10470871
• 负责人: YOU-YANG ZHAO
• 金额: $ 63.12万
• 依托单位: LURIE CHILDREN'S HOSPITAL OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10470871
• 关键词: Angiogenic Factor; Animal Model; Attenuated; Blood Vessels; Bone Marrow; Bone Marrow Cells; CCAAT-Enhancer-Binding Proteins; CSF1R gene; CXCL12 gene; CXCR4 Receptors; CXCR4 gene; Cell Lineage; Cell Proliferation; Cells; Cessation of life; Clinical; Coculture Techniques; Disease; Endothelial Cells; Exhibits; G-Protein-Coupled Receptors; Genetic; Goals; Hematopoietic; Hypoxia; Hypoxia Inducible Factor; IGF1 gene; IGF1R gene; Insulin-Like Growth Factor I; Lesion; Lung; Mediating; Modeling; Molecular; Molecular Target; Morbidity - disease rate; Mus; PIK3CG gene; Pathogenesis; Pathogenicity; Patients; Pharmacology; Prevention; Procollagen-Proline Dioxygenase; Production; Protein Isoforms; Pulmonary Vascular Resistance; Pulmonary vessels; Rattus; Role; Sampling; Signal Transduction; Smooth Muscle Myocytes; Structure of parenchyma of lung; Therapeutic; Vascular remodeling; base; clinically relevant; druggable target; effective therapy; inhibitor; lung hypoxia; macrophage; mortality; mouse model; neointima formation; novel; novel therapeutic intervention; premature; primary pulmonary hypertension; progenitor; pulmonary arterial hypertension; pulmonary vascular remodeling; reconstitution; right ventricular failure; single-cell RNA sequencing; translational potential

Pulmonary arterial hypertension (PAH) is characterized by progressive increase of pulmonary vascular resistance and obliterative vascular remodeling that causes right heart failure and premature death. Given the underlying molecular mechanisms of obliterative vascular remodeling remain enigmatic, current therapies have not targeted the fundamental disease modifying mechanisms and hence only resulted in a modest improvement in the morbidity and mortality. We have recently shown that Egln1Tie2Cre mice exhibit unprecedented spontaneous severe PAH and obliterative pulmonary vascular remodeling including neointima formation, and vascular occlusion as seen in patients with idiopathic PAH (IPAH) and PHD2 expression is diminished in ECs of occlusive pulmonary vessels of IPAH patients. This renewal proposal is based on our fundamental new observations that 1) genetic depletion of macrophages (Mφ) with the MaFIA mice inhibited obliterative vascular remodeling and attenuated PAH in Egln1Tie2Cre/MaFIA mice; 2) Single cell RNA sequencing analysis identified an emerging subpopulation of PAH-specific progenitor Mφ in Egln1Tie2Cre lungs; 3) CD206+ Mφ accumulated in the vascular lesions of Egln1Tie2Cre lungs expressed abundantly angiogenic factors inducing PASMC proliferation; 4) genetic disruption of the GPCR-dependent p110γ isoform of PI3K in Egln1Tie2Cre mice inhibited the production of these factors and obliterative vascular remodeling. Thus, we hypothesize that marked accumulation of CD206+ Mφ derived from progenitor Mφ in pulmonary vascular lesions induces obliterative pulmonary vascular remodeling and severe PAH through p110γPI3K-dependent induction of pro-PAH factors via EC-Mφ interaction. Studies in Aim 1 will determine the fundamental role of CD206+ Mφ subpopulation in promoting obliterative pulmonary vascular remodeling and severe PAH. We will employ single cell RNA sequencing, lineage tracing and genetic depletion approaches to determine the causal role of CD206+ Mφ and pMφ in mediating obliterative pulmonary vascular remodeling. In Aim 2, we will delineate the molecular basis of CD206+ Mφ in mediating obliterative pulmonary vascular remolding and explore the translational potential of targeting these molecular mechanisms for treatment of PAH. The molecular mechanisms identified in mouse models will be validated in SuHx PAH rats. The clinical relevance will also be determined with PASMCs and lung tissues of IPAH patients. We expect that the proposed studies have significant translational potential by delineating the molecular and cellular mechanisms of obliterative vascular remodeling, identifying druggable targets, and exploring novel pharmacological agents that can pharmacologically inhibit/reverse vascular remodeling for the prevention and treatment of PAH in patients.

肺动脉高压（PAH）的特征是肺血管的逐渐增加 抗性和客观的血管重塑会导致正确的心力衰竭和过早死亡。 鉴于闭塞性血管重塑的潜在分子机制仍然神秘， 当前的疗法尚未针对改变基本疾病的机制，因此仅针对 导致发病率和死亡率有所改善。我们最近表明egln1tie2cre 小鼠暴露了前所未有的赞助严重PAH和闭塞性肺血管重塑 在特发性PAH（IPAH）和 IPAH患者闭塞性肺部视频的EC中PHD2表达降低。这个更新 提案是基于我们基本的新观察，即1）巨噬细胞的遗传耗竭（Mφ） 黑手党小鼠抑制了闭塞性血管重塑，并减弱了egln1tie2cre/mafia的PAH 小鼠； 2）单细胞RNA测序分析确定了PAH特异性的新兴亚群 EGLN1TIE2CRE肺中的祖细胞Mφ； 3）CD206+Mφ积聚在EGLN1TIE2CRE的血管病变中 肺表达了绝对的血管生成因子诱导的PASMC增殖。 4）遗传破坏 PI3K在EGLN1TIE2CRE小鼠中的GPCR依赖性P110γ同工型抑制了这些因素的产生 和闭塞的血管重塑。那就是我们假设CD206+Mφ的明显积累 源自祖细胞Mφ的肺血管病变会影响闭塞性肺血管 通过P110γPI3K依赖Pro-PAH因子通过EC-Mφ通过P110γPI3K诱导的重塑和严重的PAH 相互作用。 AIM 1中的研究将确定CD206+Mφ亚群的基本作用 促进闭塞性肺血管重塑和严重的PAH。我们将使用单细胞RNA 测序，谱系跟踪和遗传部署方法确定CD206+的因果作用 Mφ和PMφ进行介导的闭塞性肺血管重塑。在AIM 2中，我们将描绘 CD206+Mφ的分子基础在介导的闭塞性肺血管恢复并探索 靶向这些分子机制以治疗PAH的电位。分子 小鼠模型中确定的机制将在SUHX PAH大鼠中进行验证。临床相关性将 还可以用IPAH患者的PASMC和肺组织确定。我们期望拟议的研究 通过描述分子和细胞机制具有显着的翻译潜力 闭塞性血管重塑，识别可药物的靶标和探索新型药理 可以物理抑制/反向血管重塑以预防和治疗的药物 患者的PAH。