SK channel antagonists as novel bronchodilators for asthma

SK通道拮抗剂作为治疗哮喘的新型支气管扩张剂

基本信息

批准号：
8770358
负责人：
ROBERT BRENNER
金额：
$ 22.13万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
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：
2014-07-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8770358
关键词：
Ablation Acetylcholine Acute Adrenergic Agonists Adverse effects Affect Affinity Agonist Airway Resistance Albuterol Animal Model Animals Apamin Asthma Biological Assay Blood Vessels Boxing Bronchoconstriction Bronchodilator Agents CCL4 gene Ca(2+)-Transporting ATPase Calcium Calcium Signaling Cells Cessation of life Chronic Chronic Obstructive Airway Disease Clinic Cytoplasm Effectiveness Electrophysiology (science)Equilibrium Goals Image Immunofluorescence Immunologic In Vitro Individual Inflammation Isometric Contraction Isometric Exercise Knockout Mice Lung Measurement Membrane Modeling Mus Muscle Muscle relaxation phase Papio Plethysmography Potassium Channel Primates Proton-Translocating ATPases Pump Pyroglyphidae Relaxation Reliance Research Research Personnel Reticulum Risk SK potassium channel Sarcoplasmic Reticulum Severities Signal Pathway Slice Smooth Muscle Myocytes Tachyphylaxis Techniques Therapeutic Time aerosolized antiport antiporter asthma inhaler base constriction extracellular in vivo novel public health relevance receptor research study respiratory smooth muscle

项目摘要

DESCRIPTION (provided by applicant): The long-term goal of this proposal is to understand the mechanism of action of calcium signaling pathways in airway smooth muscle in order to identify novel bronchodilators for the clinic. The immediate goals for this proposal are twofold. The research will provide an understanding (at the cellular level) of how a novel bronchodilator, UCL 1684, modulates SK channels and causes airway smooth muscle relaxation. The research will determine the mechanism by which SR SK potassium channels affect sarcoplasmic reticulum and cytosolic calcium load, excitability and contractility of ASM cells using calcium imaging and electrophysiology of airway smooth muscle cells. Second, the research will investigate UCL 1684 efficacy as a bronchodilator in vivo in animal models of asthma and models of ¿2 agonist tachyphylaxis. The approach will be to use whole animal plethysmography, and the forced oscillation techniques on asthmatic mice to evaluate UCL 1684 effects on airway severity and airway resistance, respectively. In addition, the experiments will examine UCL1684 effects on remodeling during asthma with a particular emphasis on its effects on airway muscle remodeling.

描述（由申请人提供）：该提案的长期目标是了解气道平滑肌中钙信号通路的作用机制，以便为临床确定新型支气管扩张剂。该提案的近期目标有两个。研究将（在细胞水平）了解新型支气管扩张剂 UCL 1684 如何调节 SK 通道并导致气道平滑肌松弛。该研究将确定 SR 的机制。其次，该研究将利用气道平滑肌细胞的钙成像和电生理学来研究 UCL 1684 在哮喘动物模型和哮喘模型中作为支气管扩张剂的体内功效。 ¿该方法将使用整体动物体积描记法和对哮喘小鼠的强制振荡技术来分别评估 UCL 1684 对气道严重程度和气道阻力的影响。此外，实验还将检查 UCL1684 对哮喘期间重塑的影响。特别强调其对气道肌肉重塑的影响。