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

基本信息

批准号：
10316765
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
项目类别：
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/10316765
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 Heart failure 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/antagonist lung hypoxia macrophage mortality mouse model neointima formation novel novel therapeutic intervention premature primary pulmonary hypertension progenitor pulmonary arterial hypertension reconstitution single-cell RNA sequencing

项目摘要

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）的特点是肺血管进行性增加阻力和闭塞性血管重塑导致右心衰竭和过早死亡。鉴于闭塞性血管重塑的潜在分子机制仍然是个谜，目前的治疗方法并未针对基本的疾病改变机制，因此只能我们最近表明 Egln1Tie2Cre 导致发病率和死亡率略有改善。小鼠表现出自发性严重 PAH 和闭塞性肺血管重塑包括特发性肺动脉高压 (IPAH) 患者中出现的新内膜形成和血管闭塞，以及 IPAH 患者闭塞肺血管的 EC 中 PHD2 表达减少。该提案基于我们的基本新观察：1) 巨噬细胞的遗传耗竭 (Mφ) MaFIA 小鼠抑制 Egln1Tie2Cre/MaFIA 中的闭塞性血管重塑并减弱 PAH 小鼠；2) 单细胞 RNA 测序分析发现了 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丰富的血管生成因子，诱导 PASMC 增殖；4) 基因破坏 Egln1Tie2Cre 小鼠中 GPCR 依赖性 p110γ PI3K 亚型抑制了这些因子的产生因此，我们追求 CD206+ Mφ 的显着积累。源自肺血管病变中的祖细胞 Mφ 诱导肺血管闭塞通过 EC-Mφ 诱导 p110γPI3K 依赖性 PAH 因子，从而重塑和严重 PAH 目标 1 的研究将确定 CD206+ Mφ 亚群在相互作用中的基本作用。我们将使用单细胞 RNA 促进闭塞性肺血管重塑和严重 PAH。测序、谱系追踪和遗传消除方法以确定 CD206+ 的因果作用 Mφ 和 pMφ 在介导闭塞性肺血管重塑中的作用在目标 2 中，我们将描述 CD206+ Mφ介导闭塞性肺血管重塑的分子基础并探讨针对这些分子机制治疗 PAH 的转化潜力。小鼠模型中确定的机制将在 SuHx PAH 大鼠中得到验证，其临床相关性将得到验证。我们期望所提出的研究也可以通过 PASMC 和 IPAH 患者的肺组织来确定。通过描述分子和细胞机制具有显着的转化潜力闭塞性血管重塑、确定药物靶标并探索新的药理学可以药理学抑制/逆转血管重塑以预防和治疗的药物患者 PAH 的情况。