The long-term objective of this proposal is to develop a detailed understanding of the role of specific Ca/2+ pumps in cardiovascular and pulmonary physiology in vivo. The Ca/2+-transporting ATPases being studied are the sarco(endo)plasmic reticulum Ca/2+-ATPases (SERCAs), which sequester Ca/2+ in intracellular storage organelles, and the plasma membrane Ca/2+-ATPases (PMCAs), which extrude Ca/2+ from the cell. It is clear that SERCAs and PMCAs serve as effector molecules controlling critical aspects of Ca/2+ homeostasis and signaling, and excitation- contraction coupling in muscle; however, the specific roles of individual isoforms are poorly understood. To obtain this information we are developing mouse models with mutations in each of the Ca/2+ pumps. We have prepared mice with SERCA2, SERCA3, and PMCA2 null mutations, and have demonstrated defective cardiac function in SERCA2 heterozygous mutants and defective endothelium and epithelium dependent relaxation of vascular and pulmonary smooth muscle in SERCA3 null mutants.
In aim 1 we will develop mice with null mutations in the PMCA1 and PMCA4 genes, and will also develop a mouse with a modified PMCA1 gene that will produce only the ubiquitous PMCA1b variant, and not the variants with an acidic calmodulin binding domain that are restricted to excitable tissues. These experiments will test the general hypotheses that individual Ca/2+ pumps serve essential housekeeping on organ-specific functions, and may reveal unexpected phenotypes that yield insights regarding the specific functions of these pumps.
In aim 2 we will analyze the developmental and histopathological consequences of mutations in each of the Ca/2+ pumps, and will perform studies using both the intact animal and isolated tissues to assess the physiological role of these pumps in cardiovascular and pulmonary tissues. These experiments will test the hypotheses that SERCA and PMCA pumps regulate cardiac contractility and pulmonary and vascular smooth muscle tone and contractility, which in turn affects cardiac function, airway resistance, and arterial blood pressure. We anticipate that the six mutant mouse lives developed in this proposal will become valuable models for analysis of the mechanisms by which Ca/2+-transporting ATPases modulate physiological functions of cardiovascular, pulmonary, and other tissues.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Experimental Cardiovascular Sciences Study Section (ECS)
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Lin, Michael
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University of Cincinnati
Schools of Medicine
United States
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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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