DAMP Signaling Mediates HIMF-induced Pulmonary Hypertension

DAMP 信号介导 HIMF 诱导的肺动脉高压

基本信息

批准号：
10206240
负责人：
Roger A Johns
金额：
$ 45.49万
依托单位：
JOHNS HOPKINS UNIVERSITY
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：
2018-08-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10206240
关键词：
Acetylation Animal Model Apoptosis Attenuated Autophagocytosis BMPR2 gene Biological Blood Vessels Cell Nucleus Cell Proliferation Cell physiology Cells Clinical Cytokine Signaling Cytoplasm Development Diabetes Mellitus Disease Down-Regulation Epigenetic Process Etiology Event Exocytosis FOXO1A gene Feedback Functional disorder Gene Expression Genetic Transcription Goals HMGB1 Protein HMGB1 gene Histologic Homologous Gene Human Hypoxia Immune Immune response In Vitro Inflammation Inflammatory Inflammatory Response Injury Interleukin-2 Lead Lung Malignant Neoplasms Mediating Mediator of activation protein Modification Molecular Mus Nuclear Nuclear Translocation Pathologic Patients Pattern Peripheral Blood Mononuclear Cell Play Process Production Property Proteins Publishing Pulmonary Hypertension Pulmonary artery structure Receptor Activation Regulation Resistance Rodent Rodent Model Role S100 Calcium Binding Protein S100 Proteins S100A11 gene SIRT1 gene Scleroderma Serum Signal Transduction Signaling Molecule Signaling Protein Slide Smooth Muscle Myocytes Specimen Structure of parenchyma of lung Vascular remodeling Work autocrine bone morphogenetic protein receptors cell motility clinically significant diagnostic biomarker extracellular hemodynamics immunoregulation in vivo mouse resistin-like alpha novel therapeutic intervention novel therapeutics paracrine receptor for advanced glycation endproducts resistin response trafficking vascular inflammation

项目摘要

SUMMARY Hypoxia-induced mitogenic factor (HIMF; also known as FIZZ1 or resistin-like molecule-) is critical to pulmonary hypertension (PH) development in rodent models, and our work suggests that HIMF may trigger a positive feedback loop to amplify the vascular inflammation required for remodeling. We have implicated the human homolog of HIMF, human resistin (hresistin) in human idiopathic and scleroderma related PH. Several downstream vascular and immune processes critical to rodent and human PH are activated by HIMF and hresistin but the manner in which HIMF/hresistin initiates these responses in a pathologic manner remains unknown. Damage-associated molecular pattern molecules (DAMPs), including high mobility group box (HMGB)1 and S100 calcium binding proteins, act as endogenous danger signals to regulate the subsequent inflammatory response through an autocrine and paracrine manner via activation of the receptor for advanced glycation end-products (RAGE). We now show HIMF and hresistin-induced HMGB1 and S100A11 activation in human vascular and immune cells related to PH and in PH animal models. However the mechanism of HIMF/hresistin regulation of this response and the function of the HIMF/DAMP/RAGE signaling axis during PH development remain unclear. In preliminary studies, we found that HIMF signaling activates HMGB1/RAGE axis in vivo and in vitro in association with suppressed sirtuin (Sirt)1, enhanced autophagy, attenuated expression of forkhead box O (FoxO)1 and bone morphogenetic protein receptor (BMPR)2, and hyper- proliferation of pulmonary artery smooth muscle cells (PASMC). In addition, in our preliminary studies another DAMP, the S100A11, also has been found to increase in peripheral blood mononuclear cells of PH patients. In this proposal, we hypothesize that HIMF/hresistin activated DAMP signaling mediates the cross- talk between vascular cells and immune cells, initiates an autophagic response, and downregulates FoxO1 and BMPR2, thereby contributing to PH pathophysiology. We will investigate the role of DAMPs in HIMF-induced inflammatory response and subsequent vascular remodeling by illustrating their cellular and molecular signaling processes initiated by HIMF and elucidating the underlying mechanism. The three related specific aims are directed at understanding: (1) the roles of HIMF in mediating the intracellular and extracellular activity and the epigenetic modification of DAMP molecules; (2) the downstream events of the HIMF/DAMP signaling axis, including autophagy/apoptosis regulation, BMPR2 and FoxO1 downregulation and their possible interaction; and (3) the expression/production of DAMPs and their downstream mediators in PH development, as well as the correlation of these molecules in existing clinical PH patient specimens. The goal of this proposal is to further clarify the relation between the immunomodulatory properties of HIMF and the etiology of PH, and thereby to explore a novel therapeutic approach for PH and other vascular inflammation-related diseases.

概括缺氧诱导的有丝分裂因子（HIMF；也称为 FIZZ1 或抵抗素样分子-α）对于啮齿动物模型中肺动脉高压（PH）的发展，我们的工作表明 HIMF 可能会引发正反馈环路放大了重塑所需的血管炎症。 HIMF 的人类同源物，人类特发性和硬皮病相关 PH 中的人类抵抗素 (hresistin)。 HIMF 激活对啮齿动物和人类 PH 至关重要的下游血管和免疫过程， hresistin，但 HIMF/hresistin 以病理方式启动这些反应的方式仍然存在未知的损伤相关分子模式分子（DAMP），包括高迁移率族盒。 (HMGB)1和S100钙结合蛋白，作为内源性危险信号来调节随后的通过激活晚期受体，通过自分泌和旁分泌方式产生炎症反应我们现在显示 HIMF 和 hresistin 诱导的 HMGB1 和 S100A11 激活。然而，人类血管和免疫细胞与 PH 以及 PH 动物模型中的机制有关。 HIMF/hresistin 对该反应的调节以及 PH 期间 HIMF/DAMP/RAGE 信号轴的功能在初步研究中，我们发现 HIMF 信号激活 HMGB1/RAGE。体内和体外轴与抑制的沉默调节蛋白（Sirt）1相关，增强自噬，减弱叉头框 O (FoxO)1 和骨形态发生蛋白受体 (BMPR)2 的表达，以及超另外，在我们的初步研究中，肺动脉平滑肌细胞（PASMC）的增殖。 DAMP（S100A11）也被发现会增加 PH 患者的外周血单核细胞。在这个提案中，我们研究了 HIMF/hresistin 激活的 DAMP 信号传导介导的交叉血管细胞和免疫细胞之间的对话，启动自噬反应，并下调 FoxO1 和 BMPR2，从而促进 PH 病理生理学我们将研究 DAMP 的作用。通过说明其在 HIMF 诱导的炎症反应和随后的血管重塑中的作用 HIMF 启动的细胞和分子信号传导过程并阐明其潜在机制三个相关的具体目标旨在理解：（1）HIMF 在以下方面的作用： (2)介导DAMP分子的细胞内和细胞外活性以及表观遗传修饰； HIMF/DAMP 信号轴的下游事件，包括自噬/凋亡调节、BMPR2 和 FoxO1 下调及其可能的相互作用；以及 (3) DAMP 的表达/产生及其可能的相互作用； PH发展中的下游介质，以及这些分子与现有临床PH的相关性该提案的目的是进一步阐明免疫调节之间的关系。 HIMF 的特性和 PH 的病因学，并探索治疗 PH 和 PH 的新方法其他血管炎症相关疾病。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

EXPRESS: Right Heart in Pulmonary Hypertension: From Adaptation to Failure.

EXPRESS：肺动脉高压中的右心：从适应到衰竭。

DOI：
发表时间：
2019-04-03
期刊：
影响因子：
2.6
作者：
Ren, Xianfeng;Johns, Roger A;Gao, Wei Dong
通讯作者：
Gao, Wei Dong

Resistin-Like Molecule α Dysregulates Cardiac Bioenergetics in Neonatal Rat Cardiomyocytes.

抵抗素样分子 α 调节新生大鼠心肌细胞中的心脏生物能学。

DOI：
发表时间：
2021
期刊：
影响因子：
0
作者：
Tao, Bingdong;Kumar, Santosh;Gomez;Fan, Chunling;Zhang, Ailan;Skinner, John;Hunter, Elizabeth;Yamaji;Samad, Idris;Hillel, Alexander T;Lin, Qing;Zhai, Wenqian;Gao, Wei Dong;Johns, Roger A
通讯作者：
Johns, Roger A

Human Resistin Induces Cardiac Dysfunction in Pulmonary Hypertension.

人类抵抗素在肺动脉高压中诱发心脏功能障碍。

DOI：
发表时间：
2023-03-21
期刊：
影响因子：
5.4
作者：
Lin, Qing;Kumar, Santosh;Kariyawasam, Udeshika;Yang, Xiaomei;Yang, Wei;Skinner, John T;Gao, Wei Dong;Johns, Roger A
通讯作者：
Johns, Roger A