Wednesday, January 15, 2025 1/15/2025

Islet Dysregulation in Infants with Congenital Hyperinsulinism

Award Number: R01DK056268
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 Congenital hyperinsulinism (HI) is the most common cause of persistent hypoglycemia in infants and children. In the last 20+ years a total of 9 genetic loci have been associated with HI, however, in approximately 40-50% of cases a genetic cause is not identified. The elucidation of the molecular mechanisms responsible for HI is of great importance to guide the development of novel therapies and eventually, a cure. Building on the success of the previous cycles of this award, we propose a comprehensive approach to examine the mechanisms of disease for two novel forms of HI that we have previously mapped to specific genomic loci by linkage analysis and whole exome sequencing. In addition, we propose a broad discovery effort for novel mechanisms of disease by performing deep genotyping and phenotyping of both individuals and isolated islets in cases with negative genetic testing on constitutional DNA. Our overall hypothesis is that genetic testing negative HI cases can be explained by novel genetic loci encompassing factors important for ß-cell function and by somatic mutations of known HI genes. To test this hypothesis, we propose two aims: to examine the mechanisms responsible for dysregulated insulin secretion by novel genetic loci identified in families with dominantly-inherited HI: Hexokinase 1 and PASK; to identify the role of post-zigotic mutations in HI; and to continue our discovery efforts through a comprehensive approach to examine genomics and functionomics of HI by deep genotyping and functional evaluations of affected individuals and their pancreatic islets. This study will expand our understanding of the molecular genetics and pathophysiology of HI and will facilitate the identification of new genetic causes and potential new therapeutic targets for this devastating disease. The discovery of novel HI loci may lead to a better understanding of the mechanisms regulating insulin secretion and may benefit the development of new therapies not only for HI, but also for 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: 2024 ( Subtotal = $628,722 )
2024	2024	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	25	8/27/2024	NON-COMPETING CONTINUATION	$628,722
														Subtotal = $628,722

Issue Date FY: 2023 ( Subtotal = $694,490 )
2023	2023	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	24	8/10/2023	NON-COMPETING CONTINUATION	$694,490
														Subtotal = $694,490

Issue Date FY: 2022 ( Subtotal = $928,666 )
2022	2022	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	23	8/12/2022	NON-COMPETING CONTINUATION	$928,666
2022	2020	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	21	10/30/2021	COMPETING CONTINUATION	$12,974
2022	2018	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	20	10/30/2021	NON-COMPETING CONTINUATION	-$12,974
														Subtotal = $928,666

Issue Date FY: 2021 ( Subtotal = $941,039 )
2021	2021	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	22	8/6/2021	NON-COMPETING CONTINUATION	$737,330
2021	2021	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	22	8/9/2021	SUPPLEMENT FOR EXPANSION	$203,709
														Subtotal = $941,039

Issue Date FY: 2020 ( Subtotal = $748,419 )
2020	2020	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	21	9/14/2020	COMPETING CONTINUATION	$748,419
2020	2018	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	20	4/16/2020	NON-COMPETING CONTINUATION	$0
2020	2018	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	20	9/13/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $748,419

Issue Date FY: 2019 ( Subtotal = $0 )
2019	2018	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	20	3/1/2019	NON-COMPETING CONTINUATION	$0
2019	2018	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	20	4/22/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2008 ( Subtotal = $616,416 )
2008	2008	CHILDREN'S HOSPITAL OF PHILADELPHIA	34TH ST & CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	10	7/18/2008	NON-COMPETING CONTINUATION	$616,416
														Subtotal = $616,416

Issue Date FY: 2007 ( Subtotal = $610,372 )
2007	2007	CHILDREN'S HOSPITAL OF PHILADELPHIA	34TH ST & CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	9	5/14/2007	NON-COMPETING CONTINUATION	$610,372
														Subtotal = $610,372

Issue Date FY: 2006 ( Subtotal = $607,900 )
2006	2006	CHILDREN'S HOSPITAL OF PHILADELPHIA	34TH ST & CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	6/12/2006	NON-COMPETING CONTINUATION	$607,900
														Subtotal = $607,900

Issue Date FY: 2005 ( Subtotal = $601,514 )
2005	2005	CHILDREN'S HOSPITAL OF PHILADELPHIA	34TH ST & CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	7	6/6/2005	NON-COMPETING CONTINUATION	$601,514
														Subtotal = $601,514

Issue Date FY: 2004 ( Subtotal = $597,704 )
2004	2004	CHILDREN'S HOSPITAL OF PHILADELPHIA	34TH ST & CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	5/17/2004	COMPETING CONTINUATION	$597,704
														Subtotal = $597,704

Issue Date FY: 2003 ( Subtotal = $370,888 )
2003	2003	CHILDREN'S HOSPITAL OF PHILADELPHIA	34TH ST & CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	7/25/2003	NON-COMPETING CONTINUATION	$370,888
														Subtotal = $370,888

Issue Date FY: 2002 ( Subtotal = $363,449 )
2002	2002	CHILDREN'S HOSPITAL OF PHILADELPHIA	34TH ST & CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	7/17/2002	NON-COMPETING CONTINUATION	$363,449
														Subtotal = $363,449

Issue Date FY: 2001 ( Subtotal = $356,227 )
2001	2001	CHILDREN'S HOSPITAL OF PHILADELPHIA	34TH ST & CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	9/12/2001	NON-COMPETING CONTINUATION	$356,227
														Subtotal = $356,227

Issue Date FY: 2000 ( Subtotal = $349,211 )
2000	2000	CHILDREN'S HOSPITAL OF PHILADELPHIA	34TH ST & CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	7/31/2000	NON-COMPETING CONTINUATION	$349,211
														Subtotal = $349,211

Issue Date FY: 1999 ( Subtotal = $357,366 )
1999	1999	CHILDREN'S HOSPITAL OF PHILADELPHIA	34TH ST & CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	8/2/1999	NEW	$357,366
														Subtotal = $357,366

Grand Total All Awards = $8,772,383

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Islet Dysregulation in Infants with Congenital Hyperinsulinism

Award Number: R01DK056268

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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