Molecular Regulation of Pulmonary Vascular KCa Channel

肺血管 KCa 通道的分子调控

• 批准号: 8288668
• 负责人: DAVID N. CORNFIELD
• 金额: $ 47.84万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8288668
• 关键词: Accounting; Acute; Address; Adult; African American; Aging; Air; Asthma; Binding; Birth; Blood; Blood Pressure; Blood Vessels; Blood flow; Calcium; Cells; Characteristics; Chronic Obstructive Airway Disease; Cystic Fibrosis; Data; Diastolic Hypertension; Disease; Environment; Environmental air flow; Epigenetic Process; Estradiol; Genes; Genetic; Genetic Polymorphism; Hour; Human; Hypertension; Hypoxia; Hypoxia Inducible Factor; Infant; Investigation; Ion Channel; Laboratories; Life; Liquid substance; Lung; Mediating; MicroRNAs; Modeling; Modification; Molecular; Morbidity - disease rate; Mus; Muscle Cells; Neonatal; Nitric Oxide; Oxygen; Pathologic; Perinatal; Persistent Fetal Circulation Syndrome; Physiological; Play; Potassium; Potassium Channel; Predisposition; Preventive; Pulmonary Circulation; Pulmonary Hypertension; Pulmonary Vascular Resistance; Pulmonary artery structure; Rattus; Regulation; Resistance; Rest; Risk; Role; Ryanodine; Severities; Sex Characteristics; Smooth Muscle Myocytes; Stimulus; Testing; Transcriptional Regulation; Vascular Diseases; Vasodilation; Work; airway hyperresponsiveness; base; fetal; gain of function; hypoxia inducible factor 1; in utero; large-conductance calcium-activated potassium channels; loss of function; novel; pressure; primary pulmonary hypertension; promoter; respiratory smooth muscle; response; transcription factor; treatment strategy; vasoconstriction; voltage

DESCRIPTION (provided by applicant): The present proposal seeks to address the molecular regulation of the calcium-sensitive potassium (BKCa) channel, an ion channel that is ubiquitously expressed in smooth muscle cells (SMC) and determines, to a meaningful degree, vascular SMC tone. Prior work from our lab has demonstrated a developmentally regulated and biologically imperative role for the BKCa channel in pulmonary artery (PA) SMC, as physiologic stimuli such as an acute increase in oxygenation, ventilation, and nitric oxide cause perinatal pulmonary vasodilation, at least in part, through activation of the BKCa channel. The gating characteristics of the channel are modified by several subunits, with the most widely expressed, the ¿1 subunit, enhancing calcium sensitivity of the channel and thereby dampening the response to constrictor stimuli. ¿1 subunit expression has physiologic implications as gain-of-function polymorphisms in the KCNMB1 gene protect against diastolic hypertension, and absence of the ¿1 subunit in mice causes hypertension. The subunit likely has implications for airways reactivity as a specific polymorphism in African Americans increases the risk for severe asthma. How ¿1 subunit expression is regulated and whether it plays a role in determining pulmonary vascular tone remains unexplored. Based on compelling preliminary evidence demonstrating that hypoxia induces an increase in ¿1 expression that is mediated by hypoxia-inducible factor-1¿ in PASMC, we formulated the overall hypothesis that in PASMC: (i) the capacity for hypoxia to increase KCNMB1 expression; and (ii) normoxic KCNMB1 expression, are developmentally regulated. In three closely related specific aims, we seek to rigorously test the working hypothesis by demonstrating in Aim 1 that loss of the ¿1 subunit accentuates hypoxic pulmonary hypertension in a murine model. In Aim 2, we plan to elucidate the transcriptional regulation that accounts for the hypoxic induction of KCNMB1. Finally, in Aim 3, we plan to address the potential that either epigenetic factors or specific micro-RNA molecules constrain KCNMB1 expression with aging. The studies to be performed will clearly establish the importance of ¿1 subunit in the regulation of pulmonary vascular tone and hold the promise of providing a novel target that might be exploited to address diseases wherein pulmonary vascular, or potentially even airway, SMC tone is pathologically increased. PUBLIC HEALTH RELEVANCE: The mass and contractile state of muscle cells that encircle the blood vessels of the lungs are increased in diseases wherein the blood pressure of the lungs is elevated. If these cells do not relax properly following the birth of infants, life-threatning illness results. The present application endeavors to identify a new strategy to decrease the tone in these cells, an approach that may be more broadly applicable to diseases such as asthma and high pressure.

描述（由申请人提供）：本提案旨在解决钙敏感性钾（BKCa）通道的分子调节，该通道是一种在平滑肌细胞（SMC）中普遍表达的离子通道，并在有意义的程度上决定血管SMC张力。我们实验室先前的工作已经证明了BKCa通道在肺动脉（PA）SMC中的发育调节和生物学强制性作用，因为生理刺激，如氧合、通气和一氧化氮的急性增加，至少部分通过激活BKCa通道引起围产期肺血管舒张。该通道的门控特性被几个亚基修饰，其中最广泛表达的是1亚基，其增强了通道的钙敏感性，从而抑制了对收缩肌刺激的反应。<$1亚基表达具有生理意义，因为KCNMB 1基因中的功能获得性多态性可防止舒张期高血压，而小鼠中<$1亚基的缺失可导致高血压。该亚基可能与气道反应性有关，因为非洲裔美国人的特定多态性增加了严重哮喘的风险。1亚基的表达是如何被调节的，以及它是否在决定肺血管张力中起作用仍然没有被探索。基于令人信服的初步证据表明，缺氧诱导的低氧诱导因子1在PASMC中介导的KCNMB 1表达增加，我们制定了总体假设，即在PASMC中：（i）缺氧增加KCNMB 1表达的能力;和（ii）常氧KCNMB 1表达，是发育调节的。在三个密切相关的具体目标中，我们试图通过在目标1中证明1亚基的缺失加重小鼠模型中的缺氧性肺动脉高压来严格检验工作假设。在目标2中，我们计划阐明占低氧诱导KCNMB 1的转录调控。最后，在目标3中，我们计划解决表观遗传因素或特定micro-RNA分子随衰老限制KCNMB 1表达的可能性。将要进行的研究将清楚地确定α 1亚基在肺血管张力调节中的重要性，并有望提供一种新的靶点，可用于治疗肺血管或潜在的甚至气道SMC张力病理性增加的疾病。 公共卫生相关性：在肺血压升高的疾病中，环绕肺血管的肌细胞的质量和收缩状态增加。如果这些细胞在婴儿出生后没有适当地放松，就会导致危及生命的疾病。本申请致力于鉴定降低这些细胞中的张力的新策略，该方法可以更广泛地适用于诸如哮喘和高压的疾病。