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Integrating genome-scale data to reveal causal mechanisms in type 2 diabetes

Award Number: U01DK105535
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2015
PERIOD OF PERFORMANCE END DATE: 04/30/2020

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Integrating genome-scale data to reveal causal mechanisms in type 2 diabetes - DESCRIPTION (provided by applicant): Type 2 diabetes has emerged as one of the leading threats to global health. The rapid rise in diabetes prevalence in both industrialized and emerging economies bears testament to the failures of prevention, and high rates of complication in those with diabetes highlight the inadequacies of current therapeutic approaches. Major gaps in our understanding of the mechanisms responsible for the development of diabetes represent obstacles to innovation with respect to novel preventative and therapeutic strategies. Human genetics provides an increasingly-powerful approach for addressing these deficiencies and providing mechanistic insights into disease that can result in health-related benefits. This proposal seeks to use information from human genetic discovery efforts that have, in recent years, identified over 100 regions of the genome which harbor DNA sequence variants influencing T2D-risk. There has been limited progress in turning these discoveries into mechanistic insights but several recent technological and analytical advances have transformed the situation, and it is these that we plan to exploit. Our first aim is to home i on the specific DNA sequence changes driving the risk-associations in these regions. The aggregation of very large genetic datasets, particularly when derived from a range of ethnic groups, makes it possible to define the subset of these variants likely to be driving the T2D-risk effect. We will take extensive genetic data sets collected as part of large international consortia and apply existing and novel approaches to derive the most precise localization of these T2D-risk variants yet obtained. Having identified these variants, the second aim is to understand the cellular processes they perturb. Recently, it has become possible to generate detailed functional maps of the genome from key diabetes- relevant human tissues, including the pancreatic islet. These maps define elements crucial for regulating cellular activity. We will use these maps to highlight the specific elements that contain T2D-causal variants, and initiate experimental studies to test the functional hypotheses that emerge. The third aim seeks to connect these T2D-associated functional elements to the specific genes, proteins, networks and pathways that mediate their effects. We will aggregate data from a variety of existing and novel public and proprietary sources, each of which provides complementary clues to the relevance of the regional genes to T2D development. Most medicines act on specific protein targets, and these efforts will result in novel protein targets that are directly implicated in human disease. An essential feature of this proposal is that it relies on extensive data sets that have already been collected, or, in some cases, are being generated with existing funding. The funding we request here will support the further integration of these data, and also enable its dissemination to the wider research community, most particularly via the AMP-T2DGENES consortium portal.


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 = $4,861 )
2022	2019	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	7/19/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2022	2018	UNIVERSITY OF OXFORD	UNIVERSITY OFFICES	OXFORD	OXFORDSHIRE			GBR	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	9/26/2022	NON-COMPETING CONTINUATION	$4,861
														Subtotal = $4,861

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2019	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	3/16/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $1 )
2020	2019	UNIVERSITY OF OXFORD	UNIVERSITY OFFICES	OXFORD	OXFORDSHIRE	OX1 2JD		GBR	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	5	7/16/2020	NON-COMPETING CONTINUATION	-$255,865
2020	2019	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	004	6	7/16/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$396,976
2020	2019	UNIVERSITY OF OXFORD	UNIVERSITY OFFICES	OXFORD	OXFORDSHIRE	OX1 2JD		GBR	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	4/1/2020	NON-COMPETING CONTINUATION	$0
2020	2019	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	005	6	8/13/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2020	2019	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	6	4/2/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$1
2020	2018	UNIVERSITY OF OXFORD	UNIVERSITY OFFICES	OXFORD	OXFORDSHIRE	OX1 2JD		GBR	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	4	7/16/2020	NON-COMPETING CONTINUATION	-$141,111
														Subtotal = $1

Issue Date FY: 2019 ( Subtotal = $255,865 )
2019	2019	UNIVERSITY OF OXFORD	UNIVERSITY OFFICES	OXFORD	OXFORDSHIRE	OX1 2JD		GBR	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	4/26/2019	NON-COMPETING CONTINUATION	$255,865
2019	2018	UNIVERSITY OF OXFORD	UNIVERSITY OFFICES	OXFORD	OXFORDSHIRE	OX1 2JD		GBR	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	2/20/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $255,865

Issue Date FY: 2018 ( Subtotal = $310,242 )
2018	2018	UNIVERSITY OF OXFORD	UNIVERSITY OFFICES	OXFORD	OXFORDSHIRE	OX1 2JD		GBR	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	6/13/2018	NON-COMPETING CONTINUATION	$310,242
														Subtotal = $310,242

Issue Date FY: 2017 ( Subtotal = $361,812 )
2017	2017	UNIVERSITY OF OXFORD	UNIVERSITY OFFICES	OXFORD	OXFORDSHIRE	OX1 2JD		GBR	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	4/27/2017	NON-COMPETING CONTINUATION	$325,630
2017	2017	UNIVERSITY OF OXFORD	UNIVERSITY OFFICES	OXFORD	OXFORDSHIRE	OX1 2JD		GBR	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	6/16/2017	NON-COMPETING CONTINUATION	$36,182
														Subtotal = $361,812

Issue Date FY: 2016 ( Subtotal = $361,802 )
2016	2016	OXFORD UNIVERSITY, DEPT OF BIOCHEMISTRY & GENETICS LAB	UNIVERSITY OFFICES	OXFORD				GBR	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	6/10/2016	NON-COMPETING CONTINUATION	$361,802
														Subtotal = $361,802

Issue Date FY: 2015 ( Subtotal = $361,813 )
2015	2015	OXFORD UNIVERSITY, DEPT OF BIOCHEMISTRY & GENETICS LAB	UNIVERSITY OFFICES	OXFORD				GBR	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	4/15/2015	NEW	$361,813
														Subtotal = $361,813

Grand Total All Awards = $1,656,396

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Integrating genome-scale data to reveal causal mechanisms in type 2 diabetes

Award Number: U01DK105535

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 05/01/2015

PERIOD OF PERFORMANCE END DATE: 04/30/2020

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