Novel signaling in chronic hypoxic responses in pulmonary arteries

肺动脉慢性缺氧反应的新信号传导

基本信息

批准号：
9186562
负责人：
YONG-XIAO WANG
金额：
$ 48.18万
依托单位：
ALBANY MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-12-15 至 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9186562
关键词：
Address Altitude Animals Calcineurin Calcium Cardiovascular system Chronic Clinic Clinical Complex Cyclin D1 Cyclins Data Development Disease Dissociation Energy Transfer Genes Heart Diseases Human Hypertension Hypoxia Immunofluorescence Immunologic In Vitro Knowledge Laser Scanning Confocal Microscopy Lung Lung diseases Mediating Mitochondria Molecular Mus Muscle Cells NF-kappa B Nuclear Organ Pathogenesis Patients Pharmaceutical Preparations Physiological Process Production Publications Pulmonary Heart Disease Pulmonary Hypertension Pulmonary artery structure Reactive Oxygen Species Residencies Rieske iron-sulfur protein Role Ryanodine Ryanodine Receptor Calcium Release Channel Secondary to Series Signal Transduction Smooth Muscle Myocytes Stabilizing Agents Staining method Stains Stress Tacrolimus Binding Proteins Testing Tetracaine Therapeutic Treatment Efficacy Vascular Diseases Work base channel blockers clinical practice constriction improved in vivo innovation knockout gene mortality novel nuclear factors of activated T-cells overexpression patch clamp prevent public health relevance pulmonary arterial hypertension receptor residence response therapeutic target vasoconstriction voltage

项目摘要

DESCRIPTION (provided by applicant): Chronic hypoxia (CH) occurs in many cardiopulmonary diseases and high altitude residency. This common clinical stress causes the remodeling, vasoconstriction and hypertension in the pulmonary artery (PA). These cellular responses primarily result from an increase in intracellular Ca concentration ([Ca2+]i, i.e., Ca2+ signaling) in PA smooth muscle cells (PASMCs). However, the underlying molecular mechanisms are not fully understood, and current therapeutic options for pulmonary hypertension (PH) are limited. Based on our preliminary data and previous publications, we propose a very innovative central hypothesis that CH causes Rieske iron-sulfur protein (RISP)-mediated mitochondrial reactive oxygen species (ROS) production, disrupts FK506 binding protein 12.6 (FKBP12.6)/ryanodine receptor-2 (RyR2) complex, causes RyR2 hyperfunction, increases Ca2+ release, activates calcineurin, cytoplasmic nuclear factor of activated T- cells (NFATc) and nuclear factor-kB (NFkB), and increases cyclin expression in PASMCs, leading to PA remodeling, contraction and hypertension. To test this exciting hypothesis, we will employ complementary, state-of-the-art laser scanning confocal microscopy, patch clamp recording, gene-manipulation, double immunofluorescence staining, florescent resonance energy transfer, and other approaches to address the following fundamental questions (Specific Aims): (1) is the FKBP12.6/RyR2 complex disrupted as a result of RISP-mediated mitochondrial ROS production in PASMCs from mice following CH; (2) does the disruption of the FKBP12.6/RyR2 complex mediate CH-induced PA remodeling, contraction and hypertension; and (3) is the role of FKBP12.6/RyR2 complex disruption in CH-induced responses in PAs mediated by the calcineurin-dependent, NF-kB/NFATc-mediated cyclin signaling axis? We fully believe that the findings from the proposed studies will greatly improve our current knowledge of the cellular molecular mechanisms for PA remodeling, constriction and hypertension, and help to fully understand what and how Ca2+ downstream signaling axis is in hypoxic. It is expected that the results may also aid in the creation of novel, specific and more effective therapeutic targets for the treatment of PAH and other relevant pulmonary vascular diseases, with a great potential for revolutionizing clinical practices.

描述（由申请人提供）：慢性缺氧（CH）发生在许多心肺疾病和高海拔居住期中。这种常见的临床应激导致肺动脉（PA）的重塑，血管收缩和高血压。这些细胞反应主要是由于细胞内Ca浓度的增加（[Ca2+] I，即Ca2+信号传导）在PA平滑肌细胞中（PASMC）。但是，尚不完全了解潜在的分子机制，并且肺动脉高压（pH）的当前治疗选择受到限制。 Based on our preliminary data and previous publications, we propose a very innovative central hypothesis that CH causes Rieske iron-sulfur protein (RISP)-mediated mitochondrial reactive oxygen species (ROS) production, disrupts FK506 binding protein 12.6 (FKBP12.6)/ryanodine receptor-2 (RyR2) complex, causes RyR2 hyperfunction, increases Ca2+激活T-细胞（NFATC）和核因子-KB（NFKB）激活钙调蛋白，细胞质核因子，并增加PASMC中的细胞周期蛋白表达，从而导致PA重塑，收缩和高血压。为了检验这一令人兴奋的假设，我们将采用互补的，最先进的激光扫描共聚焦显微镜，斑块夹记录，基因操作，双重免疫荧光染色，荧光共振能量转移以及其他方法来解决以下基本问题（特定目的）：（特定目的）：（1）是fkbbp12。 CH后，来自小鼠的PASMC中的线粒体ROS产生；（2）FKBP12.6/RYR2复合物的破坏会介导CH诱导的PA重塑，收缩和高血压；（3）FKBP12.6/RyR2复合物在由钙调蛋白依赖性的NF-KB/NFATC介导的细胞周期蛋白信号轴介导的PAS中的CH诱导响应中的作用？我们完全认为，提出的研究的发现将大大提高我们当前对PA重塑，收缩和高血压的细胞分子机制的了解，并有助于充分了解CA2+下游信号轴的缺氧。可以预期，结果还可以帮助创建新型，特定，更有效的治疗靶标，用于治疗PAH和其他相关的肺血管疾病，并具有彻底改变临床实践的巨大潜力。