Mouse Models for Ion Homeostasis Defects in Heart

心脏离子稳态缺陷的小鼠模型

• 批准号: 7923967
• 负责人: GARY EDWARD SHULL
• 金额: $ 56.38万
• 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 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7923967
• 关键词: APPBP2 gene; Acids; Adverse effects; Affect; Animal Model; Bicarbonates; Biochemical; Bumetanide; Calcium; Cardiac; Cardiomyopathies; Cardiovascular system; Carrier Proteins; Cessation of life; Chronic; Clinical; Complement; Congestive Heart Failure; Coupled; Coupling; Crystallins; Data; Death Rate; Defect; Diet; Disease; Disease susceptibility; Diuretics; Drug Delivery Systems; Echocardiography; Electrolytes; Exhibits; FLP recombinase; Fatty acid glycerol esters; Femoral vein; Fiber; Frequencies; Functional disorder; Genes; Genetic; Genetic Complementation Test; Glucose Transporter; Goals; Hand; Health; Heart; Heart Diseases; Heart failure; Heat shock proteins; Histology; Homeostasis; Hyperthyroidism; Hypertrophy; Immunoblotting; Injury; Insulin Resistance; Ion Transport; Ions; Kidney; Knock-out; Knockout Mice; Lead; Left ventricular structure; MAPK14 gene; Mechanics; Mediating; Metabolic; Metabolism; Mitochondria; Modeling; Muscle Cells; Mutate; Mutation; Myocardial Infarction; Myocardium; NHE1; Neomycin resistance gene; Oxidation-Reduction; Patients; Pattern; Performance; Pharmaceutical Preparations; Phenotype; Phosphorylation; Physiological; Predisposition; Process; Protein Isoforms; Protein Phosphatase 2A Regulatory Subunit PR53; Protein phosphatase; Proteins; Proteomics; Regulation; Relative (related person); Reperfusion Injury; Role; SLC2A1 gene; Signal Pathway; Signal Transduction; Skin; Stress; System; Testing; Transducers; Tropomyosin; Weaning; base; biological adaptation to stress; constriction; femoral artery; flexibility; glucose metabolism; heart function; improved; in vivo; inhibitor/antagonist; insight; insulin sensitivity; knockout gene; loss of function; mouse model; mutant; mutant mouse model; novel; phospholamban; pressure; protective effect; recombinase; research study; respiratory; response; stress protein; therapeutic target; uptake

Our objective is to understand the mechanisms by which the NHE1 Na/H exchanger and the AE1, AE2, AE3, and PAT1 (Slc4a1-3 and Slc26a6) Cl/HCO3 exchangers affect cardiac Ca handling, contractility, and metabolism. These acid-base transporters comprise a robust system for control of intracellular pH (pHi), but it is unlikely that this is their only function. Na/H exchange coupled with Cl/HCO3 exchange or the bumetanidesensitive NKCC1 Na-K-2Cl cotransporter operating alone mediate pHi-neutral Na-loading, which in turn can affect Ca handling and contractility. Using gene knockout mouse models, we have identified effects on Ca handling, contractility, metabolism, and susceptibility to heart disease for several of these transporters, and have evidence that AE3-mediated Cl/HCO3 exchange and Na-K-2Cl cotransport can partially compensate for loss of the other activity. In Aim 1 we will use cardiac-specific knockouts for AE1 and AE2, both of which are likely to have functional interactions with NHE1, to determine the effects of Cl/HCO3 exchange dysfunction on cardiac performance in vivo. In Aim 2, isolated myocytes and biochemical analyses will be used to determine the mechanisms by which Cl/HCO3 exchangers and NHE1 dysfunction affects Ca handling, contractility, and metabolism in heart. These experiments will test the hypotheses that modulation of sub-sarcolemmal ion concentrations by these transporters regulates both Ca handling and contractility and that NHE1 and PAT1 exert a major regulatory effect on metabolism and insulin sensitivity in heart. In Aim 3 we will test the hypotheses that specific Cl/HCO3 exchange activities contribute to hypertrophy, and that these activities and that of the loop diuretic-sensitive NKCC1 Na-K-2Cl cotransporter also affect cardiac performance and heart failure in genetic cardiomyopathy models. These studies will provide novel information about the physiological functions of this group of poorly understood transporters in heart and yield important insights about the ion transport and signaling mechanisms by which they affect Ca handling, contractility, and metabolism. In addition, these studies will identify transport activities that are cardio-protective, and therefore should not be inhibited, and transport activities that may be inhibited to elicit cardio-protection. Some of this information has important clinical implications, particularly with regard to metabolic abnormalities, including insulin resistance, in heart disease and adverse effects of loop diuretics.

我们的目标是了解NHE1 Na/H交换器和AE1，AE2，AE3和PAT1（SLC4A1-3和SLC26A6）CL/HCO3交换器影响心脏CA的处理，收缩力和代谢的机制。这些酸碱转运蛋白包含用于控制细胞内pH（PHI）的可靠系统，但这不太可能是它们的唯一功能。 NA/H交换与Cl/HCO3交换或单独使用的BumetanideNideNidesnideNidesnideNideNideNideNideNideNideNideNideNideNideNideNideNideNideNideNide-Na-K-2Cl共转运蛋白单独操作介导Phi-Na-Na-Loading，这又会影响CA的处理和收缩力。使用基因敲除小鼠模型，我们确定了这些转运蛋白的CA处理，收缩力，代谢和对心脏病的敏感性的影响，并有证据表明AE3介导的CL/HCO3交换和NA-K-2CL cotransport可以部分补偿其他活动的损失。在AIM 1中，我们将对AE1和AE2使用心脏特异性敲除，这两者都可能与NHE1具有功能相互作用，以确定CL/HCO3交换功能障碍对体内心脏性能的影响。在AIM 2中，将使用孤立的肌细胞和生化分析来确定CL/HCO3交换器和NHE1功能障碍会影响CA的处理，收缩力和内代谢的机制。这些实验将检验以下假设：这些转运蛋白调节亚甲膜离子浓度调节CA处理和收缩力，并且NHE1和PAT1对心脏中的代谢和胰岛素敏感性产生了主要的调节作用。在AIM 3中，我们将测试特定的Cl/HCO3交换活动有助于肥大的假设，并且这些活动以及循环利尿剂敏感的NKCC1 NA-K-2CL共转运蛋白的活性也会影响基因性心肌病模型的心脏表现和心力衰竭。这些研究将提供有关这一组知识转运蛋白的生理功能的新信息，并就其影响CA处理，收缩性和代谢的离子运输和信号传导机制产生重要见解。此外，这些研究将确定具有心脏保护性的运输活动，因此不应受到抑制，并且可以抑制以引起心脏保护的运输活动。其中一些信息具有重要的临床意义，尤其是在代谢异常（包括胰岛素抵抗）中，心脏病和循环利尿剂的不良影响。

项目成果

Loss of the AE3 Cl(-)/HCO(-) 3 exchanger in mice affects rate-dependent inotropy and stress-related AKT signaling in heart.

• DOI: 10.3389/fphys.2013.00399
• 发表时间: 2013
• 期刊: Frontiers in physiology
• 影响因子: 4
• 作者: Prasad V;Lorenz JN;Lasko VM;Nieman ML;Al Moamen NJ;Shull GE
• 通讯作者: Shull GE

Distinct roles of PMCA isoforms in Ca2+ homeostasis of bladder smooth muscle: evidence from PMCA gene-ablated mice.

PMCA 亚型在膀胱平滑肌 Ca2 稳态中的独特作用：来自 PMCA 基因消除小鼠的证据。

• DOI: 10.1152/ajpcell.00313.2006
• 发表时间: 2007
• 期刊: American journal of physiology. Cell physiology
• 作者: Liu,Li;Ishida,Yukisato;Okunade,Gbolahan;Pyne-Geithman,GailJ;Shull,GaryE;Paul,RichardJ
• 通讯作者: Paul,RichardJ

Maitotoxin converts the plasmalemmal Ca(2+) pump into a Ca(2+)-permeable nonselective cation channel.

Maitotoxin 将质膜 Ca(2 ) 泵转化为 Ca(2 ) 可渗透的非选择性阳离子通道。

• DOI: 10.1152/ajpcell.00252.2009
• 发表时间: 2009
• 期刊: American journal of physiology. Cell physiology
• 作者: Sinkins,WilliamG;Estacion,Mark;Prasad,Vikram;Goel,Monu;Shull,GaryE;Kunze,DianaL;Schilling,WilliamP
• 通讯作者: Schilling,WilliamP

SERCA2 Haploinsufficiency in a Mouse Model of Darier Disease Causes a Selective Predisposition to Heart Failure.

• DOI: 10.1155/2015/251598
• 发表时间: 2015
• 期刊: BioMed research international
• 作者: Prasad V;Lorenz JN;Lasko VM;Nieman ML;Huang W;Wang Y;Wieczorek DW;Shull GE
• 通讯作者: Shull GE

Ablation of plasma membrane Ca(2+)-ATPase isoform 4 prevents development of hypertrophy in a model of hypertrophic cardiomyopathy.

• DOI: 10.1016/j.yjmcc.2014.09.025
• 发表时间: 2014-12
• 期刊: Journal of molecular and cellular cardiology
• 影响因子: 5
• 作者: V. Prasad;J. Lorenz;V. Lasko;M. Nieman;Min Jiang;Xu Gao;Jack Rubinstein;D. Wieczorek;G. Shull