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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：
8874107
负责人：
ROBERT BRENNER
金额：
$ 18.54万
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 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8874107
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 Ca(2+)-Transporting ATPase Calcium Calcium Signaling Calcium-Activated Potassium Channel Cessation of life Chronic Chronic Obstructive Airway Disease Clinic Effectiveness Electrophysiology (science)Goals Health Image Immunofluorescence Immunologic In Vitro Individual Inflammation Isometric Contraction Isometric Exercise Knockout Mice Lung Measurement Membrane Modeling Mus Muscle Muscle Contraction Muscle function Muscle relaxants Muscle relaxation phase Papio Plethysmography Potassium Channel Primates Proton-Translocating ATPases Pyroglyphidae Relaxation Research Research Personnel Risk SK potassium channel Sarcoplasmic Reticulum Severities Signal Pathway Slice Smooth Muscle Myocytes Tachyphylaxis Techniques Therapeutic Time aerosolized antiporter asthma inhaler asthmatic base constriction in vivo novel 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 ß2 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）：本提案的长期目标是了解气道平滑肌钙信号通路的作用机制，以便为临床鉴定新型支气管扩张剂。这项提议的直接目标是双重的。该研究将提供一种理解（在细胞水平上）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。本研究将通过钙成像和气道平滑肌细胞电生理，确定SR - SK钾通道影响肌浆网和胞质钙负荷、ASM细胞的兴奋性和收缩性的机制。其次，该研究将在哮喘动物模型和ß2激动剂速速反应模型中研究UCL 1684作为体内支气管扩张剂的疗效。本研究将采用全动物体积描记法和哮喘小鼠强制振荡法分别评价UCL 1684对气道严重程度和气道阻力的影响。此外，实验将检查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。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Bis-Quinolinium Cyclophane Blockers of SK Potassium Channels Are Antagonists of M3 Muscarinic Acetylcholine Receptors.

DOI：
10.3389/fphar.2020.552211
发表时间：
2020
期刊：
Frontiers in pharmacology
影响因子：
5.6
作者：
Bugay V;Wallace DJ;Wang B;Salinas I;Chapparo AP;Smith HR;Dube PH;Brooks EG;Berg KA;Brenner R
通讯作者：
Brenner R

Knockout of the BK β2 subunit reveals the importance of accessorizing your channel.