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Alcohol-induced Skeletal Muscle Insulin Insensitivity in SIV/HIV: Myotube-derived Extracellular Vesicle-mediated Mechanisms

Award Number: F30AA029358
ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $55,736 )
2024	2024	LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER NEW ORLEANS	433 BOLIVAR ST RM 619	NEW ORLEANS	LA	70112	ORLEANS	USA	Alcohol Research Programs	000	4	7/16/2024	NON-COMPETING CONTINUATION	$55,736
														Subtotal = $55,736

Issue Date FY: 2023 ( Subtotal = $42,047 )
2023	2023	LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER-NEW ORLEANS	433 BOLIVAR ST STE 815	NEW ORLEANS	LA	70112	ORLEANS	USA	Alcohol Research Programs	000	3	7/7/2023	NON-COMPETING CONTINUATION	$42,047
														Subtotal = $42,047

Issue Date FY: 2022 ( Subtotal = $38,605 )
2022	2022	LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER-NEW ORLEANS	433 BOLIVAR ST STE 815	NEW ORLEANS	LA	70112	ORLEANS	USA	Alcohol Research Programs	000	2	7/22/2022	NON-COMPETING CONTINUATION	$38,605
														Subtotal = $38,605

Issue Date FY: 2021 ( Subtotal = $37,889 )
2021	2021	LOUISIANA STATE UNIVERSITY SYSTEM	433 BOLIVAR ST STE 815	NEW ORLEANS	LA	70112	ORLEANS	USA	Alcohol Research Programs	001	1	7/21/2021	NEW	$0
2021	2021	LOUISIANA STATE UNIVERSITY SYSTEM	433 BOLIVAR ST STE 815	NEW ORLEANS	LA	70112	ORLEANS	USA	Alcohol Research Programs	000	1	7/21/2021	NEW	$37,889
														Subtotal = $37,889

Grand Total All Awards = $174,277

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Alcohol-induced Skeletal Muscle Insulin Insensitivity in SIV/HIV: Myotube-derived Extracellular Vesicle-mediated Mechanisms

Award Number: F30AA029358

ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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