MK2 and pulmonary hypertension

MK2 和肺动脉高压

• 批准号: 10491169
• 负责人: Mahendra Damarla
• 金额: $ 75.43万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10491169
• 关键词: AQP1 gene; Apoptosis; Apoptotic; Blood capillaries; C-terminal; CASP3 gene; Cell Death; Cell Survival; Cell physiology; Cells; Complex; Consensus; Coupled; Cytosol; Data; Development; Disease; Down-Regulation; Endothelial Cells; Exposure to; Failure; Family; Growth; Hypoxia; Hypoxia Inducible Factor; Immunoprecipitation; In Vitro; Laboratories; Lesion; Link; MAPKAPK2 gene; Mediating; Membrane Proteins; Modeling; Molecular; Molecular Chaperones; Mus; Nuclear; Nuclear Translocation; Pathogenesis; Pathway interactions; Patients; Phenotype; Play; Predisposition; Protein-Serine-Threonine Kinases; Proteins; Publishing; Pulmonary Hypertension; Pulmonary arterial remodeling; Rattus; Regulation; Resistance; Rodent Model; Role; SU 5416; Signal Pathway; Site; Stimulus; Stress; Tail; Tars; Testing; Ubiquitination; Up-Regulation; Vascular Proliferation; Vascular remodeling; base; cell growth; experimental study; in vivo Model; inhibitor; insight; interdisciplinary approach; lung hypoxia; lung injury; lung microvascular endothelial cells; novel; novel therapeutics; prevent; protein expression; protein protein interaction; pulmonary arterial hypertension; pulmonary arterial pressure; pulmonary vascular cells; right ventricular failure; therapeutic target; transcription factor; water channel

PROJECT SUMMARY Pulmonary arterial hypertension (PAH) is a deadly, debilitating disease with no cure. The development of PAH is associated with robust structural remodeling of the small pulmonary arteries, including intimal thickening and formation of vaso-occlusive lesions. In addition to abnormally increased proliferation of vascular cells, failure of appropriate apoptosis (i.e., apoptotic resistance) contributes to remodeling via lack of cell turnover. Our laboratory recently discovered that the expression of the protein-serine kinase, MAPKAP2 (MK2), is markedly downregulated in pulmonary microvascular endothelial cells (PMVECs) from the SU5416+hypoxia (SuHx) rat model of PAH. Little is known regarding the control of MK2 expression; however, our preliminary data indicate that MK2 is regulated by hypoxia-inducible factors (HIFs), a family of transcription factors suggested to be involved in the development of PAH. Loss of MK2 is associated with cytosolic sequestration of caspase-3, preventing apoptosis. Moreover, we linked reduced MK2 levels with upregulation of the water channel, aquaporin 1 (AQP1), which we previously have shown promotes pro-proliferative effects in pulmonary vascular cells. However, the mechanism by which MK2 might influence AQP1 expression is unknown. Based on these data, we hypothesize that in PAH PMVECs, HIF-dependent downregulation of MK2 results in cytosolic sequestering of caspase-3 and upregulation of AQP1, leading to apoptotic resistance and hyperproliferation, respectively. Thus, the Aims of this study are to: 1) determine whether loss of MK2 during PAH mediates cytosolic sequestering of caspase-3; 2) determine the mechanism by which MK2 controls AQP1 expression; and 3) evaluate whether increasing the expression of MK2 reverses changes in cell phenotype and vascular remodeling in PAH. We will use a comprehensive, multidisciplinary approach combining in vitro and in vivo models of PAH to explore the effect of modulating factors in this pathway on PMVEC cell function and development and reversal of PAH. The successful completion of the proposed studies will impact the field by: 1) describing signaling pathways mediated by MK2 that are involved in the development and progression of PAH; 2) providing new information regarding regulation of MK2 expression; 3) identifying specific interactions between caspase-3, MK2 and AQP1 that are responsible for controlling caspase-3 subcellular localization and AQP1-induced PMVEC growth; and 4) directing subsequent studies aimed at development of new therapeutics.

项目摘要 肺动脉高压（PAH）是一种致命的，使人衰弱的疾病，无法治愈。发展的发展 PAH与小肺动脉的鲁棒结构重塑有关，包括内膜 血管熟悉病变的增厚和形成。除了异常增加血管增殖 细胞，适当凋亡（即凋亡耐药性）的失败有助于通过缺乏细胞进行重塑 周转。我们的实验室最近发现蛋白质丝氨酸激酶MapKap2的表达 （MK2）在肺微血管内皮细胞（PMVEC）中明显下调 SU5416+PAH的低氧（SUHX）大鼠模型。关于MK2表达的控制知之甚少。然而， 我们的初步数据表明，MK2受到低氧诱导因素（HIF）的调节，这是一个转录家族 建议与PAH的发展有关的因素。 MK2的损失与胞质有关 caspase-3的隔离，防止凋亡。此外，我们将降低的MK2水平与上调联系起来 我们先前已显示的水通道1（AQP1）的水通道1（AQP1）促进了促增强效应 在肺血管细胞中。但是，MK2可能影响AQP1表达的机制是 未知。基于这些数据，我们假设在PAH PMVEC中，HIF依赖于MK2的下调 导致caspase-3的胞质隔离和AQP1的上调，从而导致凋亡抗性和 分别优化。因此，这项研究的目的是：1）确定MK2是否在 PAH介导caspase-3的胞质隔离； 2）确定MK2控制AQP1的机制 表达; 3）评估增加MK2的表达是否会逆转细胞表型的变化和 PAH中的血管重塑。我们将采用一种全面的，多学科的方法，结合体外和 PAH的体内模型探索该途径中调节因子对PMVEC细胞功能和 PAH的发展和逆转。拟议研究的成功完成将通过以下方式影响该领域 1）描述由MK2介导的信号通路参与 pah; 2）提供有关MK2表达调节的新信息； 3）确定特定的互动 在负责控制caspase-3亚细胞定位的CASPASE-3，MK2和AQP1之间 AQP1诱导的PMVEC增长； 4）指导旨在开发新的研究 疗法。