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Autophagy/antioxidant response coupling in pancreatic beta-cell homeostasis regulation

Award Number: R01DK124380
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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Autophagy/antioxidant response coupling in pancreatic beta-cell homeostasis regulation - The incidence of diabetes in the US population has been rapidly increasing over the past several decades. Type 1 diabetes is a result of β-cell death, or apoptosis of the insulin-producing cells in the pancreas. While there are a variety of known triggers for β-cell apoptosis, most feed into pathways that lead to increased generation of reactive oxygen species (ROS) in the β-cell. Unchecked accumulation of β-cell ROS can disrupt cellular homeostasis, cause oxidative damage, and lead to apoptosis. A typical adaptive response to increased ROS includes activation of the transcription factor NRF2, which stimulates the cell-protective antioxidant response and restores homeostasis. We recently found that tandem activation of interleukin-6 (IL-6) receptor signaling and NRF2 in the β-cell couples autophagy to the antioxidant response, reduces β-cell ROS, and protects against oxidative damage to increase β-cell survival in vivo. Importantly, we discovered that non-canonical actions of NRF2 in the mitochondria were associated with the stimulation of mitophagy, the selective degradation of mitochondria by autophagy. Collectively, these data lead to our hypothesis that autophagy and antioxidant response are coupled in the β-cell and that orchestration of these processes is essential for maintenance of β-cell homeostasis and diabetes prevention. The proposed work will incorporate both in vitro experiments using cultured islets/ β-cells and in vivo analyses in mice. We will pursue the following specific aims: 1) To identify the mechanism controlling NRF2 mitochondrial translocation and determine its role in β-cell autophagy/antioxidant response coupling; and 2) To determine the in vivo contributions of autophagy/antioxidant response coupling to β-cell homeostasis. Overall, these experiments will define the role of autophagy/antioxidant response coupling in the adaptive response to stress and allow us to identify therapeutic targets guiding the signaling events within the islet under conditions known to lead to β-cell failure. My background in β-cell biology and resources within the Indiana Center for Diabetes and Metabolic Diseases makes me uniquely suited to accomplish the aims of this project.


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: 2025 ( Subtotal = $356,625 )
2025	2025	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	1/22/2025	NON-COMPETING CONTINUATION	$356,625
														Subtotal = $356,625

Issue Date FY: 2024 ( Subtotal = $380,400 )
2024	2024	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	5/3/2024	NON-COMPETING CONTINUATION	$23,775
2024	2024	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	2/19/2024	NON-COMPETING CONTINUATION	$356,625
														Subtotal = $380,400

Issue Date FY: 2023 ( Subtotal = $396,250 )
2023	2023	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	8/21/2023	SUPPLEMENT FOR EXPANSION	$35,524
2023	2023	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	1/20/2023	NON-COMPETING CONTINUATION	$396,250
2023	2023	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	3	8/24/2023	SUPPLEMENT FOR EXPANSION	-$35,524
														Subtotal = $396,250

Issue Date FY: 2022 ( Subtotal = $396,250 )
2022	2022	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	4/12/2022	NON-COMPETING CONTINUATION	$39,625
2022	2022	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	2/10/2022	NON-COMPETING CONTINUATION	$356,625
														Subtotal = $396,250

Issue Date FY: 2021 ( Subtotal = $396,250 )
2021	2021	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	3/12/2021	NEW	$396,250
														Subtotal = $396,250

Grand Total All Awards = $1,925,775

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Autophagy/antioxidant response coupling in pancreatic beta-cell homeostasis regulation

Award Number: R01DK124380

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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