Document text
Principal Investigator: Brianna Leilani Bourgeois
Organization: LSU HEALTH SCIENCES CENTER
Fiscal Year: 2022
Award: $38,605
Funding agency: National Institute on Alcohol Abuse and Alcoholism
Abstract
The primary purpose of this Ruth L. Kirschstein NRSA F30 application is to provide the groundwork that will
prepare the applicant for an academic medical career. Much of the applicant’s career development will come
from work in High Priority HIV/AIDS comorbidity-related research, and she will have the invaluable opportunity
to carry out high quality research using a well-established preclinical model of chronic binge alcohol (CBA) and
simian immunodeficiency virus (SIV) infection. At-risk alcohol use is twice as likely in people living with HIV
(PLWH) as it is in the general population. PLWH on antiretroviral therapy (ART) have a near normal life
expectancy, but there is an increase in prevalence of metabolic comorbidities, requiring a need for research
studying pathophysiological mechanisms of metabolic dysregulation in the context of HIV. Studies from our group
have shown that at-risk alcohol use and CBA is associated with impaired insulin/glucose dynamics in PLWH and
in SIV-infected macaques, respectively. Skeletal muscle (SKM) is a major site of insulin-dependent glucose
uptake, and preclinical studies indicate that alcohol decreases SKM insulin sensitivity. Preliminary data
generated for this application suggest that CBA dysregulates proteins in the insulin signaling pathway in SKM,
further indicating that alcohol leads to SKM dysfunction. With previous work from our group demonstrating that
CBA-mediated alterations in myotubes reflect what is seen in SKM, we will utilize cultured myotubes to reflect
changes seen in SKM in our proposed experiments. Extracellular vesicles (EVs) mediate cellular changes in
pathologic and therapeutic conditions by transporting bioactive cargo, including microRNAs (miRNAs), between
cells. miRNAs are small non-coding RNAs that regulate gene expression and are differentially expressed by
CBA and insulin resistance. Preliminary and previous data suggests that CBA leads to lower expression of the
SKM specific miRNA-206 in plasma EVs and the SKM of SIV-infected macaques, and miRNA-206 is implicated
in SKM insulin-dependent glucose uptake. Taken together, our preliminary data and published literature support
the hypothesis, that alcohol-mediated alterations in myotube extracellular vesicle miRNA cargo contribute
to decreased myotube insulin sensitivity in SIV infection. The proposed study will employ a wide variety of
state-of- the-art techniques to test the hypothesis using two specific aims: (1) CBA-administration alters myotube-
derived EV profile in SIV-infected macaques, and (2) myotube-derived EV miRNA cargo of CBA-administered
SIV-infected macaques decreases myotube insulin sensitivity. Findings from the proposed studies will provide
insight on the role of EVs in alcohol-mediated SKM insulin insensitivity in SIV infection. Additionally, the proposed
project aims to illustrate the therapeutic potential of EVs in improving alcohol-mediated SKM dysfunction. With
a strong mentoring team committed to developing a well-rounded physician scientist, completion of the proposed
training plan in High Priority HIV/AIDS comorbidity-related research will ensure that the applicant is ready to
embark on a career in academic medicine.
Terms: <AIDS Virus><AIDS/HIV><AIDS/HIV problem><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Affect><Alcohol Chemical Class><Alcohol Drinking><Alcohol consumption><Alcoholic Hepatitis><Alcohols><Blood Plasma><Cell Body><Cell Communication and Signaling><Cell Signaling><Cell to Cell Communication and Signaling><Cell-Cell Signaling><Cells><Chronic><D-Glucose><Data><Dextrose><Dysfunction><Electroporation><Embryonic Muscle Cells><Endocrine><Endocrinology><Ensure><EtOH drinking><EtOH use><Ethanol-induced hepatitis><Fellowship><Fostering><Functional RNA><Functional disorder><Funding><Future><GLUT 4 protein><GLUT4><GLUT4 gene><GLUT4 protein><Gene Expression><General Population><General Public><Glucose><HIV><HIV/AIDS><HIV/AIDS problem><Health Sciences><Hepatic Disorder><Human Immunodeficiency Viruses><Humulin R><Immunoblotting><Impairment><In Vitro><Insulin><Insulin Resistance><Insulin Signaling Pathway><Intracellular Communication and Signaling><LAV-HTLV-III><Laboratories><Life Expectancy><Lipid Bilayers><Lipids><Literature><Liver diseases><Louisiana><Lymphadenopathy-Associated Virus><M mulatta><M. mulatta><Macaca><Macaca mulatta><Macaque><Measures><Mediating><Medical><Medical Research><Medicine><Mentors><Metabolic><Metabolism and Endocrinology><Mice><Mice Mammals><Micro RNA><MicroRNA Expression Profiling><MicroRNAs><Modeling><Murine><Mus><Muscle><Muscle Fibers><Muscle Tissue><Myoblasts><Myotubes><NIAAA><NRSA><National Institute on Alcohol Abuse and Alcoholism><National Research Service Awards><Non-Coding><Non-Coding RNA><Non-Polyadenylated RNA><Non-translated RNA><Noncoding RNA><Nontranslated RNA><Novolin R><Pancreas><Pancreatic><Pathologic><Pathway interactions><Persons><Phosphorylation><Physicians><Physiologic><Physiological><Physiopathology><Plasma><Plasma Serum><Pre-Clinical Model><Preclinical Models><Precursor Muscle Cells><Prevalence><Protein Phosphorylation><Proteins><Publishing><RNA><RNA Gene Products><Regular Insulin><Regulation><Research><Reticuloendothelial System, Serum, Plasma><Rhabdomyocyte><Rhesus Macaque><Rhesus Monkey><Ribonucleic Acid><Role><SIV><Sarcoglycans><Scientist><Signal Transduction><Signal Transduction Systems><Signaling><Simian Immunodeficiency Viruses><Site><Skeletal Fiber><Skeletal Muscle><Skeletal Muscle Cell><Skeletal Muscle Fiber><Skeletal Myoblasts><Skeletal Myocytes><Techniques><Testing><Therapeutic><Training><Universities><Untranslated RNA><Viral Diseases><Virus Diseases><Virus-HIV><Voluntary Muscle><Western Blotting><Western Immunoblotting><Work><alcohol ingestion><alcohol intake><alcohol product use><alcohol related research><alcohol research><alcohol risk><alcohol use><alcoholic beverage consumption><alcoholic drink intake><anti-retroviral therapy><anti-retroviral treatment><antiretroviral therapy><antiretroviral treatment><base><biological signal transduction><career><career development><co-morbid><co-morbidity><comorbidity><differential expression><differentially expressed><electroporative delivery><ethanol consumption><ethanol drinking><ethanol ingestion><ethanol intake><ethanol product use><ethanol research><ethanol use><experiment><experimental research><experimental study><extracellular vesicles><gene electrotransfer><global miRNA profiling><glucose uptake><hepatic disease><hepatopathy><improved><in vivo><insight><insulin resistant><insulin sensitivity><insulin-responsive glucose transporter><intercellular communication><interest><lipid bilayer membrane><liver disorder><miRNA><miRNA expression profiling><miRNA sequencing><miRNA-seq><miRNAs><micro RNA expression profiling><microRNA profiling><microRNA sequencing><muscular><nano particle><nano-sized particle><nanoparticle><nanosized particle><neural><noncoding><novel><paracrine><pathophysiology><pathway><pre-clinical research><pre-clinical study><preclinical research><preclinical study><protein blotting><relating to nervous system><research study><social role><stem><training opportunity><transcriptional differences><translational potential><translational study><translational therapeutics><translational therapy><vesicle release><vesicular release><viral infection><virus infection><virus-induced disease>