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Targeting transient receptor potential channels to suppress proviral mitochondrial fission and mitophagy in order to mitigate CVB pancreatitis

Award Number: R01DK125692
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY Coxsackievirus B (CVB) is a common human pathogen that can cause an array of inflammatory diseases such as meningo-encephalitis, myocarditis and pancreatitis. CVB has strong tropism to the pancreas and as such is a leading cause of viral pancreatitis. Acute pancreatitis can sometimes be severe, which leads to systemic inflammation, damage to other organs and death in 10-30% of patients. Children are at higher risk for lethal CVB pancreatitis. CVB can also cause chronic pancreatitis, which is a persistent inflammation of the pancreas that is a risk factor for pancreatic cancer. Treatments for severe viral pancreatitis generally aim to mitigate symptoms, however there is a lack of effective interventions that limit disease progression. In a recent study we had reported that CVB type 3 (CVB3) infection causes mitochondrial fission with subsequent activation of mitophagy in infected cells. We surmise that CVB3 triggers this in order to become engulfed in mitophagosomes which become expelled from the host cell as virus-laden extracellular vesicles. Specifically blocking mitochondrial fission or mitophagy pathways disrupts this process and attenuates infection. In recent reports, the transient receptor potential (TRP) ion channels have been shown to influence mitochondrial dynamics. The capsaicin and heat receptor TRPV1 can trigger mitochondrial depolarization which leads to mitochondrial fragmentation. We have found that inhibiting TRPV1 not only prevents CVB3-induced mitochondrial fission, but also significantly reduces infection in vitro. Similarly, activating the TRPV1 antagonist TRPM8 using menthol also greatly blunts infection. We tested the effects of oral menthol treatments in a mouse model of pancreatic CVB3 infection and saw that menthol blunts pancreatic damage and viral load. There is very limited data on how TRP channels influence viral infection. Understanding how these pathways influence CVB3 infection will allow us to establish novel antiviral treatments (such as menthol) to be used to suppress CVB3 pancreatitis as well as other CVB3- induced diseases.


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 = $295,931 )
2024	2024	UNIVERSITY OF ALABAMA	301 ROSE ADMIN BLDG	TUSCALOOSA	AL	35487	TUSCALOOSA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	12/29/2023	NON-COMPETING CONTINUATION	$277,435
2024	2024	UNIVERSITY OF ALABAMA	801 UNIVERSITY BLVD	TUSCALOOSA	AL	35401	TUSCALOOSA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	5/30/2024	NON-COMPETING CONTINUATION	$18,496
														Subtotal = $295,931

Issue Date FY: 2023 ( Subtotal = $313,692 )
2023	2023	UNIVERSITY OF ALABAMA	301 ROSE ADMIN BLDG	TUSCALOOSA	AL	35487	TUSCALOOSA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	1/18/2023	NON-COMPETING CONTINUATION	$313,814
2023	2021	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	11/21/2022	NEW	-$122
														Subtotal = $313,692

Issue Date FY: 2022 ( Subtotal = $327,800 )
2022	2022	UNIVERSITY OF ALABAMA	301 ROSE ADMIN BLDG	TUSCALOOSA	AL	35487	TUSCALOOSA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	005	2	5/6/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$273,881
2022	2022	UNIVERSITY OF ALABAMA	301 ROSE ADMIN BLDG	TUSCALOOSA	AL	35487	TUSCALOOSA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	2	3/31/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$32,780
2022	2022	UNIVERSITY OF ALABAMA	301 ROSE ADMIN BLDG	TUSCALOOSA	AL	35487	TUSCALOOSA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	2/23/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$295,020
2022	2022	UNIVERSITY OF ALABAMA	301 ROSE ADMIN BLDG	TUSCALOOSA	AL	35487	TUSCALOOSA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	2	2/24/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2022	2021	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	004	1	5/6/2022	NEW	-$273,881
2022	2021	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	LOS ANGELES	CA	90048	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	2/23/2022	NEW	$0
														Subtotal = $327,800

Issue Date FY: 2021 ( Subtotal = $367,400 )
2021	2021	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	LOS ANGELES	CA	90048	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	2/25/2021	NEW	$367,400
														Subtotal = $367,400

Grand Total All Awards = $1,304,823

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Targeting transient receptor potential channels to suppress proviral mitochondrial fission and mitophagy in order to mitigate CVB pancreatitis

Award Number: R01DK125692

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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