Ca2+ Sparks as Regulators of Airway Contractility

Ca2 Sparks 作为气道收缩性的调节剂

基本信息

批准号：
7228897
负责人：
Ronghua ZhuGe
金额：
$ 30.15万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-06-10 至 2009-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7228897
关键词：
Address Aging Asthma Attention Biophysics Blood Pressure Brain Cardiac Cardiomegaly Cell membrane Cells Characteristics Complement component C1s Comprehension Coronary Coronary artery Coupling Development Disease Elevation Event Failure Figs - dietary Functional disorder Generations Goals Health Heart failure Hyperactive behavior Hypertension Image Imaging Techniques In Situ Intracellular Membranes Ion Channel Knockout Mice Knowledge Lead Life Localized Lung Membrane Membrane Potentials Methods Mitochondria Molecular Mus Muscle Contraction Numbers Pathogenesis Personal Satisfaction Physiological Physiology Play Preparation Regulation Relaxation Research Role Role playing therapy Ryanodine Receptor Calcium Release Channel Sarcoplasmic Reticulum Signal Transduction Slice Smooth Muscle Smooth Muscle Myocytes Spasm Speed Testing Transgenic Organisms Vascular Smooth Muscle Work digital insight intracellular protein transport large-conductance calcium-activated potassium channels mouse model novel novel therapeutics patch clamp protein localization location respiratory smooth muscle sensor spatial relationship therapeutic target voltage

项目摘要

DESCRIPTION (provided by applicant): This project seeks to understand the mechanisms by which the contractility of airway smooth muscle (ASM) is controlled and regulated. The present proposal focuses on the highly localized and short-lived Ca2+ events (Ca2+ sparks), resulting from the opening of ryanodine receptors (RyRs) in the sarcoplasmic reticulum membrane, and their interactions with nearby Ca2+-activated ion channels in the plasma membrane. As in vascular smooth muscle, Ca2+ sparks activate a small number of large-conductance K+ (BK) channels in the spark microdomain to generate spontaneous transient outward currents (STOCs) which hyperpolarize the membrane in ASM. Recently we have identified another important target of Ca2+ sparks in ASM, i.e. Ca2+-activated CI- (CIca) channels which cause spontaneous transient inward currents (STICs) and thus depolarize the membrane. Accordingly, the central hypothesis of this proposal is that Ca2+ sparks coordinate the activation of membrane channels to regulate airway contractility. An integrated approach using high-speed digital Ca2+ imaging with simultaneous patch-clamping, and also 2D and 3D protein localization, will be applied using normal and transgenic mouse models. Furthermore, a physiological airway preparation, i.e., lung slices, will be employed to investigate the role of Ca2+ sparks in regulating contractility of airways themselves. Our specific objectives are to uncover the biophysics of RyRs underlying Ca2+ sparks using our newly developed signal mass approach (Aim 1); to determine the functional and spatial relationships of RyRs to BK channels and CIca channels (Aims 2 and 3); and to determine the physiological role of Ca2+ sparks in airways (Aim 4). We expect that these studies will provide new knowledge which could lead to development of novel therapeutic approaches for asthma and other bronchospasitc disorders.

描述（由申请人提供）：该项目旨在了解控制和调节气道平滑肌（ASM）收缩力的机制。目前的提案重点关注高度局部和短暂的 Ca2+ 事件（Ca2+ 火花），该事件是由于肌浆网膜中兰尼碱受体 (RyRs) 的开放引起的，以及它们与质膜中附近 Ca2+ 激活的离子通道的相互作用。与血管平滑肌一样，Ca2+ 火花激活火花微区中的少量大电导 K+ (BK) 通道，产生自发瞬态外向电流 (STOC)，使 ASM 中的膜超极化。最近，我们发现了 ASM 中 Ca2+ 火花的另一个重要目标，即 Ca2+ 激活的 CI- (CIca) 通道，它会引起自发瞬态内向电流 (STIC)，从而使膜去极化。因此，该提议的中心假设是Ca2+火花协调膜通道的激活以调节气道收缩性。使用高速数字 Ca2+ 成像和同步膜片钳以及 2D 和 3D 蛋白质定位的综合方法将应用于正常和转基因小鼠模型。此外，还将采用生理气道准备，即肺切片，来研究 Ca2+ 火花在调节气道本身收缩性中的作用。我们的具体目标是使用我们新开发的信号质量方法揭示 Ca2+ 火花背后的 RyRs 生物物理学（目标 1）；确定 RyR 与 BK 通道和 CIca 通道的功能和空间关系（目标 2 和 3）；并确定 Ca2+ 火花在气道中的生理作用（目标 4）。我们期望这些研究将提供新知识，从而开发出治疗哮喘和其他支气管痉挛疾病的新方法。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The transmembrane protein 16A Ca(2+)-activated Cl- channel in airway smooth muscle contributes to airway hyperresponsiveness.

DOI：
10.1164/rccm.201207-1303oc
发表时间：
2013-02
期刊：
American journal of respiratory and critical care medicine
影响因子：
24.7
作者：
Cheng-Hai Zhang;Yinchuan Li;Wei Zhao;Lawrence M. Lifshitz;Hequan Li;B. Harfe;Min-Sheng Zhu;R. Zhuge
通讯作者：
Cheng-Hai Zhang;Yinchuan Li;Wei Zhao;Lawrence M. Lifshitz;Hequan Li;B. Harfe;Min-Sheng Zhu;R. Zhuge

Suppression of Ca2+ syntillas increases spontaneous exocytosis in mouse adrenal chromaffin cells.

DOI：
10.1085/jgp.200910285
发表时间：
2009-10
期刊：
The Journal of general physiology
影响因子：
0
作者：
Lefkowitz JJ;Fogarty KE;Lifshitz LM;Bellve KD;Tuft RA;ZhuGe R;Walsh JV Jr;De Crescenzo V
通讯作者：
De Crescenzo V

A C-terminally truncated mouse Best3 splice variant targets and alters the ion balance in lysosome-endosome hybrids and the endoplasmic reticulum.

C端截短的小鼠Best3剪接变体靶向并改变溶酶体-内体杂合体和内质网中的离子平衡