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Principal Investigator: Christopher G Kevil
Organization: LOUISIANA STATE UNIV HSC SHREVEPORT
Fiscal Year: 2020
Award: $191,038
Funding agency: National Institute of General Medical Sciences
PROJECT SUMMARY/ABSTRACT
The present project is part of the Centers of Biomedical Research Excellence (COBRE) grant focused on
research on redox biology mechanisms of cardiovascular disease. The objective of the COBRE Center for Redox
Biology and Cardiovascular Disease is to establish a nationally recognized research and training program that
develops federally funded junior faculty research while revealing new insights into cardiovascular pathology. One
of the major goals of this COBRE program is to advance mechanistic understanding of redox biology regulation
in cardiovascular pathophysiology. To accomplish this goal, the COBRE program provides a consistent and
robust mentorship and professional development program, funding, and core facility support to junior faculty
projects investigating the redox biology mechanisms of cardiovascular disease that will be competitive for
independent federal funding. The proposed research is part of a current, funded COBRE pilot project focused
on investigating the sex-specific effects of redox imbalances on the heart. The main goal of this proposed
supplement is to expand our current studies on sexual dimorphism. We aim to elucidate, for the first time, the
direct effects of confinement-induced mental stress on the female heart, and to test whether increased mental
stress leads to alterations in critical genes involved in antioxidant pathways in the heart. Since we are facing an
unprecedented situation involving social distancing and confinement with the COVID-19 pandemic,
understanding the long-term cardiac effects of mental stress triggered by confinement is currently of great
interest. Women are at high risk of developing cardiac events in response to mental stress. Stress levels in
women have been shown to correlate with delayed recovery, recurrence, and increased mortality after a heart
attack compared with age-matched men. However, the mechanisms underlying these sex differences are not
precise. In this proposal, we plan to evaluate the direct and long-term effects of confinement stress on the female
heart, and to test whether exposure to this stressor leads to adverse outcomes in females by altering the
expression of genes involved in maintaining the redox balance in cardiomyocytes. Our preliminary data revealed
that confinement stress induces sex-specific changes in the expression of cyclin-dependent kinase inhibitor 1A
(Cdkn1A), which activates the master regulator of the intracellular antioxidant response, nuclear factor erythroid-
2-related factor 2 (Nrf2). With the support of this supplement, if awarded, we will test if Cdkn1A in the female
heart is under the direct regulation of the glucocorticoid receptor (GR), the stress hormone receptor. Also, we
will test whether changes in the levels of Cdkn1A have effects on Nrf2 downstream signaling in the heart that
may predispose females to heart disease and its complications. The results gathered in this proposal will provide
the basis for future studies focused on whether dysregulation in Cdkn1A in the heart has predictive or therapeutic
value for cardiovascular diseases (CVD) in women with or without cardiovascular conditions who have
experienced confinement and mental stress due to the COVID-19 pandemic.
Terms: <2019 novel coronavirus><2019-nCoV><Age><American><Antioxidants><Award><Biochemical><Biology><C57BL/6 Mouse><CDK-Interacting Protein 1><CDKN1><CDKN1A><CDKN1A gene><CIP1><COBRE><COVID-19 epidemic><COVID-19 pandemic><COVID19 epidemic><COVID19 pandemic><Cardiac><Cardiac Diseases><Cardiac Disorders><Cardiac Muscle Cells><Cardiac Myocytes><Cardiac development><Cardiac health><Cardiac infarction><Cardiocyte><Cardiovascular><Cardiovascular Body System><Cardiovascular Diseases><Cardiovascular Organ System><Cardiovascular Pathology><Cardiovascular system><Cell Communication and Signaling><Cell Cycle><Cell Division Cycle><Cell Signaling><Center of Biomedical Research Excellence><Centers of Research Excellence><Clinical Data><Clinical Research><Clinical Study><Collaborations><Core Facility><Cyclin-Dependent Kinase Inhibitor 1A><DNA Damage><DNA Injury><Data><Detection><Differences between sexes><Differs between sexes><Dysfunction><Echocardiogram><Echocardiography><Emotional Stress><Endocrine Gland Secretion><Equilibrium><Estrogens><Event><Exposure to><Faculty><Female><Functional disorder><Funding><Future><Gene Expression><Genes><Glucocorticoid Receptor><Glucocorticoids><Glutathione><Goals><Grant><Harvest><Heart><Heart Diseases><Heart Muscle Cells><Heart Vascular><Heart failure><Heart health><Heart myocyte><High Risk Woman><Home><Home environment><Hormone Receptor><Hormones><Human><Infarction><Inflammatory><Injury><Intracellular Communication and Signaling><Ischemia-Reperfusion Injury><K01 Award><K01 Mechanism><K01 Program><KO mice><Knock-out Mice><Knockout Mice><Long-Term Effects><Longterm Effects><Measures><Mediating><Mentored Research Scientist Development Award><Mentored Training Award><Mentors><Mentorship><Mice><Mice Mammals><Modeling><Modern Man><Murine><Mus><Myocardial Infarct><Myocardial Infarction><NF-E2 protein><NF-E2 transcription factor><NFE2 protein><NHLBI><National Heart, Lung, and Blood Institute><Natural Disasters><Null Mouse><Oxidation-Reduction><Oxidative Stress><Pathway interactions><Physiologic><Physiological><Physiopathology><Pilot Projects><Population><Position><Positioning Attribute><Predictive Value><Predisposition><Program Development><Proteins><Provincial Government><Psyche structure><Receptor Signaling><Recovery><Recurrence><Recurrent><Redox><Regulation><Reperfusion Damage><Reperfusion Injury><Research><Research Scientist Development Award><Research Training><Risk><SARS-CoV-2><SARS-CoV2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related coronavirus 2><Severe acute respiratory syndrome coronavirus 2><Sex Differences><Sexual differences><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Social Distance><State Government><Stress><Susceptibility><Testing><Therapeutic><Therapeutic Estrogen><Therapeutic Hormone><Time><Training Programs><Transthoracic Echocardiography><Uncertainty><Up-Regulation><Upregulation><Virus><WAF1><Wildtype p53-Activated Fragment 1><Woman><Wuhan coronavirus><adverse consequence><adverse outcome><ages><anti-oxidant><anti-oxidant enzyme><antioxidant enzyme><balance><balance function><base><biological signal transduction><cardiac failure><cardiac function><cardiac infarct><cardiomyocyte><cardioprotectant><cardioprotection><cardioprotective><cardiovascular disease risk><cardiovascular disorder><cardiovascular disorder risk><cardiovascular health><circulatory system><corona virus disease 2019 epidemic><corona virus disease 2019 pandemic><coronary attack><coronary infarct><coronary infarction><coronavirus disease 2019 epidemic><coronavirus disease 2019 pandemic><doubt><experience><experiment><experimental research><experimental study><faculty research><function of the heart><gamma-L-Glu-L-Cys-Gly><gamma-L-Glutamyl-L-Cysteinylglycine><heart attack><heart disorder><heart function><heart infarct><heart infarction><heart sonography><in vivo><infarct><injuries><insight><interest><male><men><men's><mental><mortality><mouse model><murine model><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><novel><novel therapeutic approach><novel therapeutic intervention><novel therapy approach><nuclear factor-erythroid 2><oxidation reduction reaction><p21 gene><p21 protein><pathophysiology><pathway><pilot study><programs><proteotoxic><proteotoxicity><response><sex><sex dimorphism><sex-dependent differences><sex-related differences><sex-specific differences><sexual dimorphism><sexually dimorphic><social engagement><social involvement><social participation><stem><stressor><women at high risk>