Models of Ion Transport Defects in Heart and Lung

心肺离子传输缺陷模型

• 批准号: 6730771
• 负责人: GARY EDWARD SHULL
• 金额: $ 52.39万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6730771
• 关键词: acid base balance; biological models; biological signal transduction; calcium transporting ATPase; congenital disorders; electrolytes; gene targeting; genetically modified animals; heart function; ion transport; laboratory mouse; lung; model design /development; muscle function; northern blottings; polymerase chain reaction; respiratory function; sodium hydrogen exchanger; vascular smooth muscle

DESCRIPTION (provided by applicant): Our long-term objective is to develop an understanding of the physiological functions of a broad array of ion transporters that maintain acid-base, electrolyte, and Ca homeostasis in cardiovascular and pulmonary tissues in vivo. These include at least 8 HCO3 transporters, the NHE1 Na/H exchanger, the NKCC1 Na-K-2CI cotransporter, and at least 7 Ca pumps. With few exceptions, the activities of specific isoforms cannot be distinguished in vivo or in vitro. To understand the physiological role and relative importance of each transporter, we are systematically developing and analyzing gene-targeted and transgenic mouse models. We have already developed many of these models, and have identified phenotypes involving cardiac performance, ischemic-reperfusion injury, blood pressure, vascular and airway smooth muscle tone, airway anion secretion, and others. In Aim 1 we will develop knockout mice for both Na-HCO3 cotransporters and Ca pumps and transgenic mice that allow rescue of severe phenotypes for the AE1 and AE2 CI/HCO3 exchangers and NHE1 Na/H exchanger knockouts. In Aim 2 we will determine the physiological consequences of transporter dysfunction in cardiovascular tissues and lung. Specifically, we will analyze: a) cardiac function to determine whether, and to what extent, the null mutations affect cardiac performance and alter responses to ischemic-reperfusion injury and hypertrophic stimuli, b) blood pressure at the whole animal level and vascular smooth muscle contractility and ion homeostasis at the tissue level, c) pulmonary function in mechanically ventilated mice under normal conditions and following bronchoconstrictor challenge, and d) ion transport mechanisms involved in transepithelial anion currents and smooth muscle tone in isolated airway preparations. These studies will test the hypotheses that the acid-base, electrolyte, and Ca transporters being studied regulate cardiac contractility and pulmonary and vascular smooth muscle tone and contractility, which in turn affect cardiac function in health and disease, arterial blood pressure, and airway resistance. We anticipate that the new mouse lines being developed in this proposal will, like the models already developed, become valuable models for analysis of the mechanisms by which these ion transporters regulate the physiological functions of cardiovascular, pulmonary, and other tissues.

描述（由申请人提供）：我们的长期目标是对体内酸碱，电解质和Ca稳态保持在体内和肺组织中维持酸碱，电解质和Ca稳态的广泛离子转运蛋白的生理功能。其中包括至少8个HCO3转运蛋白，NHE1 NA/H交换器，NKCC1 Na-K-2CI共转运蛋白和至少7个CA泵。除少数例外，特定同工型的活性不能在体内或体外区分。为了了解每个转运蛋白的生理作用和相对重要性，我们正在系统地开发和分析靶向基因和转基因小鼠模型。我们已经开发了许多此类模型，并且已经确定了涉及心脏性能，缺血性再灌注损伤，血压，血管和气道平滑肌张力，气道阴离子分泌等的表型。在AIM 1中，我们将为Na-HCO3共转运蛋白和Ca泵和转基因小鼠开发敲除小鼠，以拯救AE1和AE2 CI/HCO3口气和NHE1 NA/H Exchanganger敲除的严重表型。在AIM 2中，我们将确定心血管组织和肺中转运蛋白功能障碍的生理后果。具体而言，我们将分析：a）心脏功能，以确定零突变是否影响心脏性能并改变对缺血性 - 灌注损伤和肥大刺激的反应，并改变反应，b）在组织水平上，整个动物水平的血压和血管平滑肌肉收缩性和离子稳态在组织水平上，并在组织水平上均可及其在机械上的正常情况，c）在机械上的效应，c）在机械上的效应，c）在机械上的效应，并在机械上划分，并在机械上划分，并在较低的情况下划分。在孤立气道制剂中，参与旋转的阴离子电流和平滑肌音的传输机制。这些研究将测试研究的假设，即被研究的酸碱，电解质和CA转运蛋白调节心脏收缩性，肺部和血管平滑肌张力和收缩力，这反过来又影响心脏功能在健康和疾病，动脉血压和气道抵抗中。我们预计，该提案中开发的新小鼠线将像已经开发的模型一样，成为分析这些离子转运蛋白调节心血管，肺部和其他组织生理功能的机制的宝贵模型。