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: 10677597
• 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/10677597
• 关键词: Angiogenic Factor; Animal Model; Attenuated; Blood Vessels; Bone Marrow; Bone Marrow Cells; CSF1R gene; CXCR4 Receptors; 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; Lesion; Lung; Macrophage; Mediating; Modeling; Molecular; Molecular Target; Morbidity - disease rate; Mus; PIK3CG gene; Pathogenesis; Pathogenicity; Patients; Prevention; Procollagen-Proline Dioxygenase; Production; Protein Isoforms; Pulmonary Vascular Resistance; Pulmonary vessels; Rattus; Role; Sampling; Signal Transduction; Smooth Muscle Myocytes; Sorting; Stromal Cell-Derived Factor 1; Structure of parenchyma of lung; Therapeutic; Vascular remodeling; clinically relevant; druggable target; effective therapy; improved; inhibitor; lung hypoxia; mortality; mouse model; neointima formation; novel; novel therapeutic intervention; pharmacologic; 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）以肺血管进行性增高为特征

项目成果

Discovery of a murine model of clinical PAH: Mission impossible?

• DOI: 10.1016/j.tcm.2016.12.003
• 发表时间: 2017-05-01
• 期刊: TRENDS IN CARDIOVASCULAR MEDICINE
• 影响因子: 9.3
• 作者: Dai, Zhiyu;Zhao, You-Yang
• 通讯作者: Zhao, You-Yang

Lipopolysaccharide-induced endotoxemia in corn oil-preloaded mice causes an extended course of lung injury and repair and pulmonary fibrosis: A translational mouse model of acute respiratory distress syndrome.

• DOI: 10.1371/journal.pone.0174327
• 发表时间: 2017
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Wu C;Evans CE;Dai Z;Huang X;Zhang X;Jin H;Hu G;Song Y;Zhao YY
• 通讯作者: Zhao YY

Prolyl-4 Hydroxylase 2 (PHD2) Deficiency in Endothelial Cells and Hematopoietic Cells Induces Obliterative Vascular Remodeling and Severe Pulmonary Arterial Hypertension in Mice and Humans Through Hypoxia-Inducible Factor-2α.

• DOI: 10.1161/circulationaha.116.021494
• 发表时间: 2016-06-14
• 期刊: Circulation
• 影响因子: 37.8
• 作者: Dai Z;Li M;Wharton J;Zhu MM;Zhao YY
• 通讯作者: Zhao YY

An unexpected role of neutrophils in clearing apoptotic hepatocytes in vivo.

• DOI: 10.7554/elife.86591
• 发表时间: 2023-09-20
• 期刊: eLife
• 影响因子: 7.7
• 作者: Cao L;Ma L;Zhao J;Wang X;Fang X;Li W;Qi Y;Tang Y;Liu J;Peng S;Yang L;Zhou L;Li L;Hu X;Ji Y;Hou Y;Zhao Y;Zhang X;Zhao YY;Zhao Y;Wei Y;Malik AB;Saiyin H;Xu J
• 通讯作者: Xu J

CD151 Maintains Endolysosomal Protein Quality to Inhibit Vascular Inflammation.

CD151 维持内溶酶体蛋白质量以抑制血管炎症。

• DOI: 10.1161/circresaha.123.323190
• 发表时间: 2024
• 期刊: Circulation research
• 影响因子: 20.1
• 作者: Chen,Junxiong;Ding,Yingjun;Jiang,Chao;Qu,Rongmei;Wren,JonathanD;Georgescu,Constantin;Wang,Xuejun;Reuter,DarleneN;Liu,Beibei;Giles,CoryB;Mayr,ChristophH;Schiller,HerbertB;Dai,Jingxing;Stipp,ChristopherS;Subramaniyan,Bhara
• 通讯作者: Subramaniyan,Bhara