CIC-3 chloride ion channels in vascular smooth muscle
血管平滑肌中的CIC-3氯离子通道
基本信息
- 批准号:7052847
- 负责人:
- 金额:$ 28.81万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1999
- 资助国家:美国
- 起止时间:1999-04-01 至 2008-03-31
- 项目状态:已结题
- 来源:
- 关键词:angiotensin IIcalmodulin dependent protein kinasecell membranechloride channelsgenetically modified animalslaboratory mousemembrane activitymuscle cellsprotein localizationprotein protein interactionprotein structure functionprotein transportrecombinant proteinssuperoxidestissue /cell culturevascular smooth musclevoltage /patch clamp
项目摘要
Chloride (CI) currents contribute to agonist-induced depolarization of vascular smooth muscle (VSM) cells. As part of the original grant proposal for which this application is a continuation, we created a mouse lacking a specific chloride channel, CIC-3 (encoded by the CIcn3 gene). Five findings from our laboratory demonstrate the importance of CIC-3 to cardiovascular function: 1) Animals lacking CIC-3 CI channels display multiple cardiovascular abnormalities including; hypertension, left ventricular hypertrophy and diastolic dysfunction, and impaired endothelium-dependent relaxation in resistance vessels, 2) CIC-3 channels are located intracellularly in resting VSM cells, but are inserted into the plasma membrane in response to All, 3) there is an unappreciated diversity of CIC-3 protein structure resulting from alternative splicing that may alter membrane trafficking, 4) Clcn3-/- cells have increased levels of intracellular reactive oxygen species (ROS), and 5) superoxide anion may pass through CIC-3 channels. There is conflicting data in the literature as to the biophysical nature of CIC-3. These inconsistencies may reflect a lack of in-depth knowledge of channel localization within the cell and the mechanisms that move the channel between cellular compartments. We will first carefully define the localization and trafficking of CIC-3. We will then test the hypothesis that the altered microvascular function observed in Clcn3-/- mice is related to the absence of a conductance that normally provides a mechanism by which superoxide anion moves across biological membranes. In this renewal application, we will; 1) Define the subcellular localization of native CIC-3 protein in murine VSM and identify factors that regulate the trafficking of CIC-3 to the plasma membrane in response to angiotensin II, 2) Define the subcellular localization of the six distinct splice variants of CIC-3 in VSM cells using FIV-driven expression of recombinant CIC-3 protein and identify motifs and physiologic factors that regulate membrane trafficking of CIC-3, and 3) Determine why intracellular ROS levels are elevated in Clcn3-/- cells and tissues and discern if this increase is physiologically relevant. The CIC-3 knockout mouse represents a novel single-gene defect model of hypertension. Careful analysis of the physiological defects in Clcn3-/- mice will yield important insight into cellular ROS metabolism and the link between ROS and high blood pressure.
氯离子(CI)电流有助于激动剂诱导血管平滑肌(VSM)细胞的去极化。作为本申请的延续的原始拨款提案的一部分,我们创建了缺乏特定氯离子通道CIC-3(由CIcn3基因编码)的小鼠。我们实验室的五项发现证明了CIC-3对心血管功能的重要性:1)缺乏CIC-3 CI通道的动物表现出多种心血管异常,包括;高血压,左室肥厚和舒张功能障碍,以及阻力血管内皮依赖性松弛受损,2)CIC-3通道位于静息VSM细胞的细胞内,但在All反应中插入质膜,3)由于选择性剪接导致CIC-3蛋白结构的多样性可能改变膜运输,4)Clcn3-/-细胞增加细胞内活性氧(ROS)水平。5)超氧阴离子可通过CIC-3通道。关于CIC-3的生物物理性质,文献中存在相互矛盾的数据。这些不一致可能反映了缺乏对细胞内通道定位和细胞间通道移动机制的深入了解。我们将首先仔细界定CIC-3的本地化和贩运。然后,我们将验证在Clcn3-/-小鼠中观察到的微血管功能改变与缺乏电导有关的假设,而电导通常提供超氧阴离子通过生物膜移动的机制。在此续期申请中,我们将:1)确定小鼠VSM中天然CIC-3蛋白的亚细胞定位,并确定响应血管紧张素II调节CIC-3向质膜运输的因子;2)利用fiv驱动表达重组CIC-3蛋白,确定CIC-3在VSM细胞中6种不同剪接变异体的亚细胞定位,并确定调节CIC-3膜运输的基元和生理因子。3)确定Clcn3-/-细胞和组织中细胞内ROS水平升高的原因,并辨别这种增加是否与生理相关。CIC-3敲除小鼠代表了一种新的高血压单基因缺陷模型。仔细分析Clcn3-/-小鼠的生理缺陷将对细胞ROS代谢以及ROS与高血压之间的联系产生重要的见解。
项目成果
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{{ truncateString('FRED S LAMB', 18)}}的其他基金
Anion channel regulation of vascular superoxide signaling in hypertension
高血压血管超氧化物信号传导的阴离子通道调节
- 批准号:
10642865 - 财政年份:2022
- 资助金额:
$ 28.81万 - 项目类别:
LRRC8 anion channels, superoxide and RhoA in diabetic erectile dysfunction
LRRC8 阴离子通道、超氧化物和 RhoA 在糖尿病勃起功能障碍中的作用
- 批准号:
10608182 - 财政年份:2022
- 资助金额:
$ 28.81万 - 项目类别:
CIC-3 chloride ion channels in vascular smooth muscle
血管平滑肌中的CIC-3氯离子通道
- 批准号:
6865460 - 财政年份:1999
- 资助金额:
$ 28.81万 - 项目类别:
C1C-3 CHLORIDE ION CHANNELS IN VASCULAR SMOOTH MUSCLE
血管平滑肌中的 C1C-3 氯离子通道
- 批准号:
2835651 - 财政年份:1999
- 资助金额:
$ 28.81万 - 项目类别:
C1C-3 CHLORIDE ION CHANNELS IN VASCULAR SMOOTH MUSCLE
血管平滑肌中的 C1C-3 氯离子通道
- 批准号:
6390327 - 财政年份:1999
- 资助金额:
$ 28.81万 - 项目类别:
CIC-3 chloride ion channels in vascular smooth muscle
血管平滑肌中的CIC-3氯离子通道
- 批准号:
6775952 - 财政年份:1999
- 资助金额:
$ 28.81万 - 项目类别:
CIC-3 chloride ion channels in vascular smooth muscle
血管平滑肌中的CIC-3氯离子通道
- 批准号:
7216399 - 财政年份:1999
- 资助金额:
$ 28.81万 - 项目类别:
C1C-3 CHLORIDE ION CHANNELS IN VASCULAR SMOOTH MUSCLE
血管平滑肌中的 C1C-3 氯离子通道
- 批准号:
6184809 - 财政年份:1999
- 资助金额:
$ 28.81万 - 项目类别:
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