With the aging of the United States population, it is estimated that the elderly (>65 years of age) will increase from 13-14% to 25% by 2035. If this trend continues, >50% of the United States population and >2 billion people worldwide will be """"""""aged"""""""" in the next 50 years. Aged individuals face formidable challenges to their health, as aging is associated with a myriad of diseases. Cardiovascular disease is the leading cause of morbidity and mortality in the United States with >50% of mortality attributed to coronary artery disease and >80% of these deaths occurring in those age 65 and older. Aged hearts are more sensitive than young hearts to ischemic insults. Several theories have been proposed to account for this aging deficit. These theories either invoke a genetic, a biochemical, a catabolic, or a physiologic component. Though the mechanisms that underlie an age-related deficit in ischemic tolerance are not clear, they likely involve abnormalities in cellular signaling and mitochondria that are a combined result of genetic, biochemical, catabolic, and physiologic deficiencies. Therapeutics that target these mechanisms have potential to rescue the aged myocardium. Our preliminary studies show that caveolin is localized to motochondria and can modulate mitochondrial function/dynamics. We propose the following hypotheses: 1) targeted cellular trafficking of caveolin to key regulatory junctions (i.e., sarcolemmal membrane and mitochondria) is a critical response to ischemic stress;2) cellular trafficking of caveolin to mitochondria is disrupted in the aged myocardium due to loss of membrane-localized caveolin;3) restoration of caveolin in distinct cellular compartments via membrane and mitochondrial targeting in aged animals may provide a means to restore tolerance to myocardial ischemia. The following specific objectives will be addressed:
Specific Aim 1 : Determine if loss of membrane-localized caveolin leads to loss of caveolin expression/caveolae formation thus limiting trafficking of caveolin to mitochondria and if membrane-targeted expression of caveolin in aged myocardium restores trafficking to mitochondria.
Specific Aim 2 : Determine if aging results in reduced mitochondria-localized caveolin to alter mitochondrial function (i.e., reactive oxygen species generation and regulation of mPTP) and mitochondrial dynamics (i.e., fusion-fission to regulate mitochondrial turnover and mitophagy) and if mitochondria-targeted caveolin expression is necessary and sufficient to restore mitochondrial function/dynamics.
Specific Aim 3 : Determine if targeted expression of caveolin in membrane or mitochondria is necessary and sufficient to restore ischemic tolerance in aged hearts.

Public Health Relevance

The current proposal aims to unravel the molecular mechanism of cardiac injury and utilize re- expression strategies to restore ischemic tolerance in the aged heart. We will assess the role of caveolins in keeping the heart """"""""young"""""""". The work described in this proposal focuses on elucidating mechanisms to support the use of caveolin proteins as novel therapeutic targets for patients at risk of myocardial ischemia and heart attacks.)

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-CVRS-B (02))
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Schwartz, Lisa
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University of California San Diego
Schools of Medicine
La Jolla
United States
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Schilling, Jan M; Head, Brian P; Patel, Hemal H (2018) Caveolins as Regulators of Stress Adaptation. Mol Pharmacol 93:277-285
Haushalter, Kristofer J; Casteel, Darren E; Raffeiner, Andrea et al. (2018) Phosphorylation of protein kinase A (PKA) regulatory subunit RI? by protein kinase G (PKG) primes PKA for catalytic activity in cells. J Biol Chem 293:4411-4421
Egawa, Junji; Schilling, Jan M; Cui, Weihua et al. (2017) Neuron-specific caveolin-1 overexpression improves motor function and preserves memory in mice subjected to brain trauma. FASEB J 31:3403-3411
Mandyam, Chitra D; Schilling, Jan M; Cui, Weihua et al. (2017) Neuron-Targeted Caveolin-1 Improves Molecular Signaling, Plasticity, and Behavior Dependent on the Hippocampus in Adult and Aged Mice. Biol Psychiatry 81:101-110
Schilling, Jan M; Patel, Hemal H (2016) Non-canonical roles for caveolin in regulation of membrane repair and mitochondria: implications for stress adaptation with age. J Physiol 594:4581-9
Jiang, Jingjing; Chan, Adriano; Ali, Sameh et al. (2016) Hydrogen Sulfide--Mechanisms of Toxicity and Development of an Antidote. Sci Rep 6:20831
Ray, Supriyo; Kassan, Adam; Busija, Anna R et al. (2016) The plasma membrane as a capacitor for energy and metabolism. Am J Physiol Cell Physiol 310:C181-92
Wagner, Nana-Maria; Gross, Eric R; Patel, Hemal H (2016) A Slick Way Volatile Anesthetics Reduce Myocardial Injury. Anesthesiology 124:986-8
Schilling, Jan M; Horikawa, Yousuke T; Zemljic-Harpf, Alice E et al. (2016) Electrophysiology and metabolism of caveolin-3-overexpressing mice. Basic Res Cardiol 111:28
See Hoe, Louise E; Schilling, Jan M; Busija, Anna R et al. (2016) Chronic ?1-adrenoceptor blockade impairs ischaemic tolerance and preconditioning in murine myocardium. Eur J Pharmacol 789:1-7

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