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The role of Spry2 in beta cell function and the unfolded protein response

Award Number: R01DK107650
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: 12/01/2015
PERIOD OF PERFORMANCE END DATE: 11/30/2021

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The role of Spry2 in beta cell function and the unfolded protein response - DESCRIPTION (provided by applicant) The pancreatic beta cell is the sole producer of physiologic levels of insulin. Type 2 diabetes develops when the pancreatic beta cell fails in the setting of increased insulin resistance. No current diabetes medication prevents beta cell failure. We propose that further understanding the pathways that control normal beta cell function will allow the more rational design of diabetes therapies that can prevent beta cell failure. To that end, we performed a whole genome RNA interference screen and identified Spry2 as a novel regulator of insulin production. Intriguingly, a single nucleotide polymorphism (SNP) near Spry2 is associated with type 2 diabetes, suggesting that it plays a role in diabetes pathogenesis. We generated a systemic genetic interaction map between top regulators of insulin transcription to understand how Spry2 might function. This map predicts that Spry2 may interact with Wfs1, a gene known to cause human diabetes via activation of the unfolded protein response (UPR). Indeed, we show that Spry2 is regulated by and regulates the UPR. The overall objective of this proposal is to define the role and mechanism of Spry2 in beta cell function, the UPR, and human diabetes. Specifically, we hypothesize that Spry2 is important for beta cell function and the UPR through an interaction with Wfs1. Our specific aims are: Aim 1: Demonstrate a role for Spry2 in beta cell function in vivo. We will characterize a beta cell specific knockout of Spry2. Aim 2: Elucidate the mechanism of Spry2 action on the UPR. We will test the functional importance of a Wfs1/Spry2 interaction and map the sites of Spry2 that are required for its modulation of the UPR. Aim 3: Test the function of Spry2 in human islets and identify the causative SNP near Spry2 that controls Spry2 expression. In the first part of the aim we will reduce Spry2 expression in human islets and measure insulin production, secretion and the unfolded protein response. In the second part of the aim, we will use genome editing to test potential causative type 2 diabetes SNPs for their ability to modulate Spry2 expression. The contribution of this proposal is the establishment of Spry2 as a new player in the beta cell UPR and in the pathogenesis of type 2 diabetes.


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: 2022 ( Subtotal = $0 )
2022	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	3/24/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $356,625 )
2020	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	3/10/2020	NON-COMPETING CONTINUATION	$35,663
2020	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	12/4/2019	NON-COMPETING CONTINUATION	$320,962
														Subtotal = $356,625

Issue Date FY: 2019 ( Subtotal = $356,625 )
2019	2019	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	11/29/2018	NON-COMPETING CONTINUATION	$356,625
														Subtotal = $356,625

Issue Date FY: 2018 ( Subtotal = $356,625 )
2018	2018	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 420	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	11/30/2017	NON-COMPETING CONTINUATION	$320,962
2018	2018	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 420	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	4/30/2018	NON-COMPETING CONTINUATION	$35,663
														Subtotal = $356,625

Issue Date FY: 2017 ( Subtotal = $356,625 )
2017	2017	UNIVERSITY OF CALIFORNIA, SAN FRANCISCO	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	6/15/2017	NON-COMPETING CONTINUATION	$35,663
2017	2017	UNIVERSITY OF CALIFORNIA, SAN FRANCISCO	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	11/17/2016	NON-COMPETING CONTINUATION	$320,962
														Subtotal = $356,625

Issue Date FY: 2016 ( Subtotal = $356,625 )
2016	2016	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	11/16/2015	NEW	$356,625
														Subtotal = $356,625

Grand Total All Awards = $1,783,125

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The role of Spry2 in beta cell function and the unfolded protein response

Award Number: R01DK107650

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: 12/01/2015

PERIOD OF PERFORMANCE END DATE: 11/30/2021

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