Ion Channels and Membrane Receptors in Pulmonary Arterial Hypertension

肺动脉高压中的离子通道和膜受体

• 批准号: 10563148
• 负责人: Jason X J Yuan
• 金额: $ 78.97万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-15 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10563148
• 关键词: Affect; Apoptosis; Apoptotic; Blood Vessels; Calcium-Sensing Receptors; Caspase; Cell Mobility; Cell Proliferation; Cell membrane; Cell physiology; Combined Modality Therapy; Data; Development; Diglycerides; Disease; Down-Regulation; G-Protein-Coupled Receptors; Genetic; Genetic Transcription; Goals; Hypertension; Inhibition of Cell Proliferation; Ion Channel; Laboratories; Lung; Lung diseases; Mediating; Membrane; MicroRNAs; Molecular; Muscle Contraction; Pathogenicity; Patients; Potassium Channel; Proliferating; Proteins; Pulmonary Hypertension; Pulmonary artery structure; Receptor Activation; Research; Role; STIM1 gene; Signal Transduction; Signal Transduction Pathway; Smooth Muscle Myocytes; TRPV1 gene; Up-Regulation; Vascular remodeling; blood pressure elevation; cell growth; cell motility; design; experience; extracellular; insight; lung hypoxia; migration; new therapeutic target; novel therapeutics; posttranscriptional; primary pulmonary hypertension; programs; pulmonary arterial hypertension; pulmonary vascular remodeling; pulmonary vasoconstriction; receptor; voltage; young woman

Project Summary/Abstract Idiopathic pulmonary arterial hypertension (IPAH) is a progressive and fatal disease. Sustained pulmonary vasoconstriction and vascular remodeling are the major causes for the elevated PVR and PAP in IPAH patients. An increase in cytosolic Ca ([Ca ]cyt) in pulmonary arterial smooth muscle cells (PASMC) is a major 2+ 2+ trigger for pulmonary vasoconstriction and for pulmonary vascular remodeling due to its stimulatory effect on PASMC proliferation and migration. Abnormally enhanced Ca2+ entry in PASMC because of upregulated expression of membrane receptors (e.g., CaSR) and Ca2+ channels (e.g., TRPC6/C3) contributes to the development and progression of PAH. Downregulation of voltage-gated K+ (Kv) channel expression and decrease in Kv currents (IK(V)) in PASMC contribute to a) increasing PASMC contraction, proliferation and migration by inducing membrane depolarization that opens voltage-dependent Ca2+ channels and raises [Ca ]cyt and b) inhibiting PASMC apoptosis by attenuating apoptotic volume decrease (AVD) and maintaining 2+ high [K ]cyt to inhibit caspases. Enhanced PASMC proliferation and inhibited PASMC apoptosis both contribute + to pulmonary vascular wall thickening. Our data show that selectively increased miRNAs are involved in posttranscriptionally downregulating Kv channels to stimulate PASMC proliferation and inhibit PASMC apoptosis in IPAH patients. Ca2+-sensing receptor (CaSR), a G protein-coupled receptor that can be activated by extracellular Ca2+, is upregulated in IPAH-PASMC compared to normal PASMC. Activation of CaSR in IPAH-PASMC induces receptor-operated Ca entry (ROCE) via diacylglycerol (DAG), while IP3-mediate active 2+ depletion of Ca2+ from the SR results in store-operated Ca2+ entry (SOCE). Extracellular Ca2+-induced CaSR activation also inhibits Kv channels and activate other signal transduction pathways to induce cell proliferation. The overall goal of this research program is to continue to investigate: i) the molecular and cellular mechanisms involved in the posttranscriptional downregulation of Kv channels and other K+ channels by miRNAs that are enhanced in PASMC from IPAH patients; ii) the genetic and molecular mechanisms responsible for the transcriptional upregulation of CaSR and receptor-operated (ROC) and store-operated (SOC) Ca2+ channels (e.g., TRPC3/C6, TRPV1, Orai1/2 and STIM1/2) in PASMC from IPAH patients; iii) the cellular and pathophysiological mechanisms involved in the CaSR-mediated functional activation of TRPC/Orai channels (and STIM1/2 oligomerization and translocation) and functional inhibition of Kv channels in PASMC from IPAH patients; and iv) the potential targets involved in the pathogenic Ca2+ signaling that can be used to develop novel therapy or combination therapy for PAH. Our laboratory has extensive research and technical experience in studying pathogenic mechanisms of IPAH and pulmonary hypertension associated with hypoxic lung disease. The forthcoming results from these studies will provide highly impactful insights into developing novel therapies for IPAH and other forms of pulmonary hypertension.

项目总结/摘要 特发性肺动脉高压（IPAH）是一种进行性、致死性疾病。持续肺动脉高压 血管收缩和血管重构是IPAH患者PVR和PAP升高的主要原因 患者肺动脉平滑肌细胞（PASMC）胞浆Ca（[Ca ]cyt）的增加是肺动脉平滑肌细胞（PASMC）的主要代谢途径。 2+ 2+ 肺血管收缩和肺血管重塑的触发，由于其刺激作用， PASMC增殖和迁移。PASMC内Ca 2+内流异常增强， 膜受体的表达（例如，CaSR）和Ca 2+通道（例如，TRPC 6/C3）有助于 PAH的发生和发展。电压门控性K+（Kv）通道表达下调， 降低PASMC的Kv电流（IK（V））有助于a）增加PASMC的收缩、增殖和 通过诱导膜去极化，打开电压依赖性Ca 2+通道， [Ca]cyt和B）通过减弱凋亡体积减少（AVD）和维持PASMC的凋亡来抑制PASMC凋亡 2个以上 高[K ]cyt抑制半胱天冬酶。增强PASMC增殖和抑制PASMC凋亡均有助于 + 肺血管壁增厚我们的数据显示选择性增加的miRNAs参与了 转录后下调Kv通道以刺激PASMC增殖并抑制PASMC IPAH患者的细胞凋亡。Ca 2+敏感受体（CaSR），一种可被激活的G蛋白偶联受体 与正常PASMC相比，IPAH-PASMC中细胞外Ca 2+的表达上调。CaSR的活化 IPAH-PASMC通过二酰基甘油（DAG）诱导受体操纵的Ca内流（ROCE），而IP 3介导的活性 2个以上 SR中Ca 2+的耗尽导致钙池操作的Ca 2+进入（SOCE）。细胞外Ca ~（2+）诱导的CaSR 激活还抑制Kv通道并激活其它信号转导途径以诱导细胞增殖。 这项研究计划的总体目标是继续研究：i）分子和细胞 Kv通道和其他K+通道的转录后下调机制， 在IPAH患者的PASMC中增强的miRNA; ii）遗传和分子机制 负责CaSR的转录上调和受体操纵（ROC）和储存操纵 (SOC)Ca 2+通道（例如，TRPC 3/C6、TRPV 1、Orai 1/2和STIM 1/2）; iii） CaSR介导的TRPC/奥赖功能激活的细胞和病理生理机制 PASMC中Kv通道（和STIM 1/2寡聚化和易位）和功能抑制 来自IPAH患者;和iv）参与致病性Ca 2+信号传导的潜在靶标，其可用于 开发PAH的新疗法或联合疗法。我们的实验室拥有广泛的研究和技术 IPAH和低氧性肺动脉高压发病机制的研究体会 肺病。这些研究即将得出的结果将为发展中国家提供极具影响力的见解。 IPAH和其他形式肺动脉高压的新疗法。

项目成果

mTOR Signaling in Pulmonary Vascular Disease: Pathogenic Role and Therapeutic Target.

• DOI: 10.3390/ijms22042144
• 发表时间: 2021-02-21
• 期刊: International journal of molecular sciences
• 影响因子: 5.6
• 作者: Babicheva A;Makino A;Yuan JX
• 通讯作者: Yuan JX

Mouse model of experimental pulmonary hypertension: Lung angiogram and right heart catheterization.

• DOI: 10.1177/20458940211041512
• 发表时间: 2021-10
• 期刊: Pulmonary circulation
• 影响因子: 2.6
• 作者: Xiong M;Jain PP;Chen J;Babicheva A;Zhao T;Alotaibi M;Kim NH;Lai N;Izadi A;Rodriguez M;Li J;Balistrieri A;Balistrieri F;Parmisano S;Sun X;Voldez-Jasso D;Shyy JY;Thistlethwaite PA;Wang J;Makino A;Yuan JX
• 通讯作者: Yuan JX

Transcriptomic profiles in pulmonary arterial hypertension associate with disease severity and identify novel candidate genes.

• DOI: 10.1177/2045894020968531
• 发表时间: 2020-10
• 期刊: Pulmonary circulation
• 影响因子: 2.6
• 作者: Romanoski CE;Qi X;Sangam S;Vanderpool RR;Stearman RS;Conklin A;Gonzalez-Garay M;Rischard F;Ayon RJ;Wang J;Simonson T;Babicheva A;Shi Y;Tang H;Makino A;Kanthi Y;Geraci MW;Garcia JGN;Yuan JX;Desai AA
• 通讯作者: Desai AA

Nicotinamide Phosphoribosyltransferase Promotes Pulmonary Vascular Remodeling and Is a Therapeutic Target in Pulmonary Arterial Hypertension.

• DOI: 10.1161/circulationaha.116.024557
• 发表时间: 2017-04-18
• 期刊: Circulation
• 影响因子: 37.8
• 作者: Chen J;Sysol JR;Singla S;Zhao S;Yamamura A;Valdez-Jasso D;Abbasi T;Shioura KM;Sahni S;Reddy V;Sridhar A;Gao H;Torres J;Camp SM;Tang H;Ye SQ;Comhair S;Dweik R;Hassoun P;Yuan JX;Garcia JGN;Machado RF
• 通讯作者: Machado RF

In Vivo and Ex Vivo Experimental Approach for Studying Functional Role of Notch in Pulmonary Vascular Disease.

研究Notch在肺血管疾病中功能作用的体内和离体实验方法。

• DOI: 10.1007/978-1-0716-2201-8_17
• 发表时间: 2022
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Jain,PriteshP;Hosokawa,Susumu;Babicheva,Aleksandra;Zhao,Tengteng;Chen,Jiyuan;Thistlethwaite,PatriciaA;Makino,Ayako;Yuan,JasonX-J
• 通讯作者: Yuan,JasonX-J