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Targeting Smooth Muscle Progenitor Cells for Treatment of Pulmonary Arterial Hypertension

靶向平滑肌祖细胞治疗肺动脉高压

基本信息

批准号：
10189689
负责人：
YOU-YANG ZHAO
金额：
$ 49.73万
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：
2018
资助国家：
美国
起止时间：
2018-06-01 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10189689
关键词：
Address Angiogenic Factor Animal Model Attenuated Blood Pressure Blood Vessels CXCL12 gene CXCR4 gene Cell Cycle Cells Cessation of life Chronic Clinical Data Diphtheria Toxin Disease Distal Endothelial Cells Endothelium FOXM1 gene Genetic Heart Hypertrophy Heart failure Hypertension Hypoxia Hypoxia Inducible Factor Lead Lesion Lung Lung diseases Mediating Modeling Molecular Monocrotaline Mus Muscle Muscle satellite cell Pathogenesis Pathologic Patients Pharmacology Play Population Procollagen-Proline Dioxygenase Pulmonary Vascular Resistance Rattus Reporter Reporting Resistance Role Smooth Muscle Smooth Muscle Actin Staining Method Smooth Muscle Myocytes Structure of parenchyma of lung Tamoxifen Testing Therapeutic Thiostrepton Tissues Vascular remodeling adenoviral-mediated alpha Actin arterial lesion arteriole diphtheria toxin receptor druggable target effective therapy forkhead protein inhibitor/antagonist intima media mortality mouse model new therapeutic target novel novel therapeutic intervention premature primary pulmonary hypertension progenitor prominin promoter pulmonary arterial hypertension receptor expression recombinant adenovirus stem cells

项目摘要

Pulmonary arterial hypertension (PAH) is characterized by obliterative pulmonary vascular remodeling and progressive elevation of pulmonary vascular resistance that leads to right heart failure and premature death. Although great efforts have been made to treat PAH, current therapies fail to reverse the disease and mortality remains high. Comprehensive understanding of the mechanisms underlying obliterative pulmonary vascular remodeling is warranted to identify druggable targets for effective treatment of PAH. Accumulation of smooth muscle cell (SMC) in the pulmonary vascular lesions is the hallmark of obliterative pulmonary vascular remodeling. We have recently identified the first mouse model of PAH [Tie2Cre-mediated disruption of Egln1, encoding hypoxia inducible factor (HIF) prolyl hydroxylase 2 (PHD2), designated Egln1Tie2Cre] with progressive obliterative vascular remodeling including vascular occlusion and plexiform-like lesion, and right heart failure, which recapitulates many features of clinical PAH. Using this mouse model as well as the Sugen/Hypoxia rat model, we identified a subpopulation of smooth muscle progenitor cells expressing CD133 (a marker of progenitor cells) (CD133+ SMPCs) which were enriched at the occlusive vascular lesions as well as the plexiform-like lesions and muscularized pulmonary arterioles. These cells expressed high levels of the cell cycle master regulator Forkhead Box M1 (FoxM1), indicating the highly proliferative potential. Genetic depletion of CD133+ cell population inhibited chronic hypoxia-induced PH. We also observed decreased vascular remodeling and PH in mice with tamoxifen-inducible deletion of Foxm1 in smooth muscle cells. Pharmacological inhibition of FoxM1 attenuated PAH in Sugen/Hypoxia-exposed rats. Thus, we hypothesize that EC-SMPC crosstalk regulates CD133+ SMPC proliferation in a FoxM1-dependent manner and thereby plays a fundamental role in the mechanisms of obliterative vascular remodeling and severe PAH. The proposed studies will address the following Specific Aims. In Aim 1, we will determine the role of smooth muscle progenitor cells in the mechanisms of pulmonary vascular remodeling and PAH. In Aim 2, we will delineate the molecular mechanisms of SMPC-mediated vascular remodeling in PAH. In Aim 3, we will explore the translational potential of targeting FoxM1 for treatment of PAH. We expect that the proposed studies have significant translational potential by elucidating the fundamental mechanisms of obliterative vascular remodeling and identifying druggable targets that can pharmacologically reverse obliterative vascular remodeling for the treatment of severe PAH in patients.

肺动脉高压（PAH）的特征是闭塞性肺血管重塑，肺血管阻力进行性升高，导致右心衰竭和过早死亡。尽管已经做出了很大的努力来治疗PAH，但目前的治疗方法未能逆转疾病和死亡率仍然很高。对肺血管闭塞性病变发生机制的全面认识重塑是必要的，以确定有效治疗PAH的药物靶点。平滑累积肺血管病变中的平滑肌细胞（SMC）是肺血管闭塞的标志重塑我们最近鉴定了PAH [Tie 2Cre]介导的Egln 1破坏的第一个小鼠模型，编码缺氧诱导因子（HIF）脯氨酰羟化酶2（PHD 2），命名为Egln 1 Tie 2Cre]，闭塞性血管重塑，包括血管闭塞和丛状病变，以及右心衰竭，其概括了临床PAH的许多特征。使用该小鼠模型以及Sugen/Hypoxia大鼠模型中，我们鉴定了一个表达CD 133的平滑肌祖细胞亚群（CD 133是一种祖细胞）（CD 133 + SMPCs），其在闭塞性血管病变处以及丛状病变和肌化肺小动脉。这些细胞表达高水平的细胞周期主调节因子叉头盒M1（FoxM 1），表明高度增殖潜力。基因耗竭 CD 133+细胞群抑制慢性缺氧诱导的PH。我们还观察到血管重塑减少和PH在平滑肌细胞中具有他莫昔芬诱导的Foxm 1缺失的小鼠中的作用。药理学抑制 FoxM 1在Sugen/缺氧暴露大鼠中减弱PAH。因此，我们假设EC-SMPC串扰以FoxM 1依赖性方式调节CD 133 + SMPC增殖，从而在闭塞性血管重构和重度PAH的机制。拟议的研究将涉及遵循具体目标。在目标1中，我们将确定平滑肌祖细胞在血管内皮细胞中的作用。肺血管重构和PAH的机制。在目标2中，我们将描述分子机制 PAH中SMPC介导的血管重塑。在目标3中，我们将探索靶向的翻译潜力 FoxM 1治疗PAH。我们预计，拟议的研究具有显着的翻译潜力，阐明闭塞性血管重塑的基本机制并确定药物靶点可逆转闭塞性血管重塑，用于治疗重度PAH患者。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Loss of Endothelial Hypoxia Inducible Factor-Prolyl Hydroxylase 2 Induces Cardiac Hypertrophy and Fibrosis.

DOI：
10.1161/jaha.121.022077
发表时间：
2021-11-16
期刊：
Journal of the American Heart Association
影响因子：
5.4
作者：
Dai Z;Cheng J;Liu B;Yi D;Feng A;Wang T;An L;Gao C;Wang Y;Zhu MM;Zhang X;Zhao YY
通讯作者：
Zhao YY

TLR4 is required for macrophage efferocytosis during resolution of ventilator-induced lung injury.