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. ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL061974-07
Application #
6835193
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Program Officer
Lin, Michael
Project Start
1999-01-01
Project End
2007-12-31
Budget Start
2005-01-01
Budget End
2005-12-31
Support Year
7
Fiscal Year
2005
Total Cost
$539,626
Indirect Cost
Name
University of Cincinnati
Department
Genetics
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Vairamani, Kanimozhi; Wang, Hong-Sheng; Medvedovic, Mario et al. (2017) RNA SEQ Analysis Indicates that the AE3 Cl-/HCO3- Exchanger Contributes to Active Transport-Mediated CO2 Disposal in Heart. Sci Rep 7:7264
Prasad, Vikram; Lorenz, John N; Lasko, Valerie M et al. (2015) SERCA2 Haploinsufficiency in a Mouse Model of Darier Disease Causes a Selective Predisposition to Heart Failure. Biomed Res Int 2015:251598
Prasad, Vikram; Lorenz, John N; Lasko, Valerie M et al. (2014) Ablation of plasma membrane Ca(2+)-ATPase isoform 4 prevents development of hypertrophy in a model of hypertrophic cardiomyopathy. J Mol Cell Cardiol 77:53-63
Schultheis, Patrick J; Fleming, Sheila M; Clippinger, Amy K et al. (2013) Atp13a2-deficient mice exhibit neuronal ceroid lipofuscinosis, limited ?-synuclein accumulation and age-dependent sensorimotor deficits. Hum Mol Genet 22:2067-82
Prasad, Vikram; Lorenz, John N; Miller, Marian L et al. (2013) Loss of NHE1 activity leads to reduced oxidative stress in heart and mitigates high-fat diet-induced myocardial stress. J Mol Cell Cardiol 65:33-42
Kim, Hyung Joon; Prasad, Vikram; Hyung, Seok-Won et al. (2012) Plasma membrane calcium ATPase regulates bone mass by fine-tuning osteoclast differentiation and survival. J Cell Biol 199:1145-58
Al Moamen, Nabeel J; Prasad, Vikram; Bodi, Ilona et al. (2011) Loss of the AE3 anion exchanger in a hypertrophic cardiomyopathy model causes rapid decompensation and heart failure. J Mol Cell Cardiol 50:137-46
Shull, Gary E; Miller, Marian L; Prasad, Vikram (2011) Secretory pathway stress responses as possible mechanisms of disease involving Golgi Ca2+ pump dysfunction. Biofactors 37:150-8
Ruminot, Iván; Gutiérrez, Robin; Peña-Münzenmayer, Gaspar et al. (2011) NBCe1 mediates the acute stimulation of astrocytic glycolysis by extracellular K+. J Neurosci 31:14264-71
Gawenis, Lara R; Bradford, Emily M; Alper, Seth L et al. (2010) AE2 Cl-/HCO3- exchanger is required for normal cAMP-stimulated anion secretion in murine proximal colon. Am J Physiol Gastrointest Liver Physiol 298:G493-503

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