Over 34 million Americans have used cocaine and >1.5 million are estimated to use this agent habitually.1 Cocaine causes severe cardiotoxicity and stimulates reactive oxygen species (ROS) production leading to left ventricle hypertrophy and dysfunction.2-4 We showed that cocaine administration to mice transgenic for HIV-1 worsens left ventricle hypertrophy, causes premature death and induces pathological changes that are more severe than those observed in wild-type mice.5 Cocaine use predisposes to human immunodeficiency virus (HIV-1) infection and HIV/AIDS.6, 7 In the developed world, HIV-1 infection is commonly treated with anti-retroviral drugs that have untoward cardiovascular effects, including cardiomyopathy.8-10 Cardiomyopathy in HIV/AIDS patients is prevalent (6%), and has a poor prognosis.11-13 Research from our laboratory and others has shown that gene products of HIV-1 and antiretroviral drugs alter mitochondrial function, stimulate mitochondrial production of ROS, and cause heart failure.14-20 The cardiovascular system is particularly prone to interactions and complications from cocaine and HIV/AIDS, however, mechanisms are poorly understood.2, 9, 10 We propose that the interaction of HIV/AIDS, antiretroviral nucleosides, and cocaine causes alterations in cardiomyocytes through undefined mechanisms that lead to cardiomyopathy and heart failure (Figure 1). The complexity of each scenario requires a systems biology approach to understand their interactions and illuminate therapeutic options. The following aims will be addressed:
Aim 1 : To define how nDNA genetic and epigenetic events in HIV/AIDS, antiretroviral therapy, and cocaine administration impact cardiomyopathy in vivo.
Aim 2 : To define genetic and epigenetic events from HIV/AIDS and cocaine that impact mRNA expression and mtDNA abundance in the heart.
Aim 3 : To prevent cardiomyopathy in HIV/AIDS, cocaine, and antiretrovirals by ameliorating oxidative stress. Our team is uniquely qualified to address the aims. We will employ a multidisciplinary approach to study transcriptional and epigenetic analysis, physiological and biochemical phenotyping and novel mathematical systems analyses to unravel this complex problem.
Cardiomyopathy is linked to HIV/AIDS and cocaine, but those clinical interactions are complex: The purpose of this application is to use a systems biological analytical approach to dissect complex interactions between pathological, physiological, biochemical and genetic events in HIV/AIDS and cocaine. Ultimately, information obtained may help to formulate testable hypotheses about pathogenesis and treatment of cardiomyopathy in HIV/AIDS and cocaine.
|Koshman, Yevgeniya E; Chu, Miensheng; Kim, Taehoon et al. (2014) Cardiomyocyte-specific expression of CRNK, the C-terminal domain of PYK2, maintains ventricular function and slows ventricular remodeling in a mouse model of dilated cardiomyopathy. J Mol Cell Cardiol 72:281-91|
|Torres, Rebecca A; Lewis, William (2014) Aging and HIV/AIDS: pathogenetic role of therapeutic side effects. Lab Invest 94:120-8|
|Remick, Joshua; Georgiopoulou, Vasiliki; Marti, Catherine et al. (2014) Heart failure in patients with human immunodeficiency virus infection: epidemiology, pathophysiology, treatment, and future research. Circulation 129:1781-9|
|Koczor, Christopher A; Torres, Rebecca A; Fields, Earl J et al. (2013) Mitochondrial matrix P53 sensitizes cells to oxidative stress. Mitochondrion 13:277-81|
|Koczor, Christopher A; Torres, Rebecca A; Fields, Earl J et al. (2013) Thymidine kinase and mtDNA depletion in human cardiomyopathy: epigenetic and translational evidence for energy starvation. Physiol Genomics 45:590-6|
|Koczor, Christopher A; Torres, Rebecca A; Fields, Earl et al. (2013) Transgenic mouse model with deficient mitochondrial polymerase exhibits reduced state IV respiration and enhanced cardiac fibrosis. Lab Invest 93:151-8|
|Koczor, Christopher A; Lee, Eva K; Torres, Rebecca A et al. (2013) Detection of differentially methylated gene promoters in failing and nonfailing human left ventricle myocardium using computation analysis. Physiol Genomics 45:597-605|
|Koczor, Christopher A; Torres, Rebecca A; Lewis, William (2012) The role of transporters in the toxicity of nucleoside and nucleotide analogs. Expert Opin Drug Metab Toxicol 8:665-76|
|Koczor, Christopher A; White, Richard C; Zhao, Peter et al. (2012) p53 and mitochondrial DNA: their role in mitochondrial homeostasis and toxicity of antiretrovirals. Am J Pathol 180:2276-83|
|Kushnir, Vitaly A; Ludaway, Tomika; Russ, Rodney B et al. (2012) Reproductive aging is associated with decreased mitochondrial abundance and altered structure in murine oocytes. J Assist Reprod Genet 29:637-42|
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