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Role of Circadian Misalignment in Beta-cell Failure in Type 2 Diabetes

Award Number: R01DK098468
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2013
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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Role of Circadian Misalignment in Beta-cell Failure in Type 2 Diabetes - PROJECT SUMMARY/ABSTRACT Pancreatic β-cell failure in a distinctive feature of Type 2 diabetes mellitus (T2DM) and therefore preservation of β-cell health has been identified as a critical barrier for the development of successful preventative and treatment strategies in T2DM. Primary features of β-cell failure include insulin secretory dysfunction, loss of transcriptional identity/β-cell dedifferentiation, and β-cell loss, with growing evidence pointing to impaired endoplasmic reticulum (ER) proteostasis as a key driver of this process. Recent evidence suggests that environmental stress conditions that produce disruptions of daily fasting/feeding circadian cycles (i.e. circadian disruption, CD) lead to glucose intolerance, hyperglycemia, and promote β-cell failure in T2DM. However, the molecular mechanisms underlying circadian control of β-cell function and ER proteostasis remain unknown. In this regard, our preliminary studies determined that CD-mediated abrogation of normal fasting/feeding cycles is a potent physiological inducer of β- cell functional failure, and this process is molecularly mediated through loss of β-cell expression/activity of circadian transcription factor D-box binding PAR bZIP transcription factor (Dbp). Therefore, the key objective of the proposal is to test the hypothesis that Dbp is an important regulator of β-cell circadian function through rhythmic activation of transcripts regulating insulin secretion and ER proteostasis, whereas loss of Dbp expression, as occurs in β-cells in response to circadian disruption and diet-induced obesity, promotes β-cell functional decline in T2DM. To address this, Specific Aim 1 will utilize novel conditional genetic loss and gain-of- function Dbp mouse models to establish a causative relationship between circadian Dbp expression and the regulation of β-cell function, ER proteostasis, and transcriptional identity. In addition, we will also examine whether Dbp regulates β-cell function and transcription in human β-cells utilizing viral gain/loss of function techniques concurrent with transplantation of human stem cell-derived β-cells into immunodeficient mice. Specific Aim 2 will utilize β-cell-specific Dbp luciferase reporter mice and systems biology multiomics approaches (RNAseq + scATAC seq) to 1) identify molecular mechanisms by which obesity disrupts circadian regulation of Dbp expression and corresponding β-cell circadian clock function, and 2) test novel strategies designed to restore normal functionality of β-cell circadian clocks in obesity as means to prevent β-cell failure in T2DM. Taken together, successful completion of proposed studies will uncover novel molecular mechanisms through which β- cells integrate and respond to circadian changes in nutritional availability and will provide potential therapeutic targets for prevention and treatment of T2DM.


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 = $516,603 )
2025	2025	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	14	6/30/2025	NON-COMPETING CONTINUATION	$516,603
2025	2022	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	11	1/31/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $516,603

Issue Date FY: 2024 ( Subtotal = $495,940 )
2024	2024	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	13	6/17/2024	NON-COMPETING CONTINUATION	$495,940
														Subtotal = $495,940

Issue Date FY: 2023 ( Subtotal = $531,953 )
2023	2023	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	12	4/19/2023	COMPETING CONTINUATION	$524,218
2023	2023	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	12	4/27/2023	COMPETING CONTINUATION	$7,735
														Subtotal = $531,953

Issue Date FY: 2022 ( Subtotal = $412,341 )
2022	2022	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	11	6/29/2022	NON-COMPETING CONTINUATION	$412,341
														Subtotal = $412,341

Issue Date FY: 2021 ( Subtotal = $412,341 )
2021	2021	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	10	6/18/2021	NON-COMPETING CONTINUATION	$412,341
														Subtotal = $412,341

Issue Date FY: 2020 ( Subtotal = $412,341 )
2020	2020	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	9	6/19/2020	NON-COMPETING CONTINUATION	$412,341
														Subtotal = $412,341

Issue Date FY: 2019 ( Subtotal = $412,341 )
2019	2019	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	8	6/25/2019	NON-COMPETING CONTINUATION	$412,341
2019	2017	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	11/14/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $412,341

Issue Date FY: 2018 ( Subtotal = $412,341 )
2018	2018	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	7	1/25/2018	COMPETING CONTINUATION	$412,341
														Subtotal = $412,341

Issue Date FY: 2017 ( Subtotal = $345,825 )
2017	2017	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	6/29/2017	NON-COMPETING CONTINUATION	$345,825
														Subtotal = $345,825

Issue Date FY: 2016 ( Subtotal = $345,825 )
2016	2016	MAYO CLINIC	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	6/29/2016	NON-COMPETING CONTINUATION	$345,825
														Subtotal = $345,825

Issue Date FY: 2015 ( Subtotal = $355,135 )
2015	2015	MAYO CLINIC	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	4	7/1/2015	NON-COMPETING CONTINUATION	$345,825
2015	2014	MAYO CLINIC	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	12/4/2014	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$296,080
2015	2014	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	12/4/2014	NON-COMPETING CONTINUATION	-$286,770
														Subtotal = $355,135

Issue Date FY: 2014 ( Subtotal = $334,950 )
2014	2014	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	6/12/2014	NON-COMPETING CONTINUATION	$334,950
														Subtotal = $334,950

Issue Date FY: 2013 ( Subtotal = $334,950 )
2013	2013	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	3/4/2013	NEW	$334,950
														Subtotal = $334,950

Grand Total All Awards = $5,322,886

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Role of Circadian Misalignment in Beta-cell Failure in Type 2 Diabetes

Award Number: R01DK098468

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2013

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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