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: 10334539
• 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/10334539
• 关键词: Affect; Apoptosis; Apoptotic; Attenuated; 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; GTP-Binding Protein alpha Subunits, Gs; Genetic; Genetic Transcription; Goals; Hypertension; Ion Channel; Ion Channel Protein; Laboratories; Lead; Lung; Lung diseases; Mediating; Membrane; MicroRNAs; Molecular; Muscle Contraction; Pathogenicity; Patients; Potassium Channel; 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; primary pulmonary hypertension; programs; pulmonary arterial hypertension; pulmonary vascular remodeling; pulmonary vasoconstriction; receptor; receptor operated channel; 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/文摘