Wednesday, December 4, 2024 12/4/2024

Intersection of signaling pathways and transcription factors regulating islet development

Award Number: R01DK118155
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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Pancreas agenesis (PA) is a developmental disorder characterized by either a reduction or complete lack of pancreatic mass. Notably, heterozygous loss of GATA6 accounts for >60% of all human pancreas agenesis cases; however, the pancreatic phenotype within each individual can be incompletely penetrant, ranging from severe neonatal diabetes to mild adult onset diabetes due to beta cell dysfunction. These findings suggest that additional genetic modifiers may contribute to the pathogenesis caused by the reduction in GATA6 expression. During the previous funding period, the collaboration between the Gadue and Sussel labs leveraged the strengths of human induced pluripotent stem cell (hiPSC)-based pancreas differentiation and in vivo murine models of development to discover robust synergy between GATA6 and retinoic acid (RA) signaling in regulating several stages of pancreas development. Our findings suggest two novel concepts: (1) an unappreciated role for RA signaling during endocrine progenitor specification and (2) synergy between RA and specifically GATA6 (but not GATA4) is required to specify beta cells in both mice and humans. The primary goals of this renewal application are to use these complementary genetic model systems to better define this synergy and elucidate the mechanisms by which the intersection of RA signaling and GATA6 regulate pancreas development. Furthermore, we will explore how human mutations in GATA6 disrupt this interaction to influence disease severity. Our published studies combined with new preliminary data in both the mice and human models has led us to hypothesize that this conserved synergy between RA signaling and GATA6 gene regulation is essential for pancreas development and the combined disruption of these pathways contributes to pancreas and islet cell development. We will test this hypothesis with the following specific aims: 1) Establish the synergistic roles of RA/GATA6 during pancreatic endocrine and β cell development and identify the specific stages of the hiPSC-derived pancreas differentiation protocol that require a combination of RA signaling and GATA6 function for optimal beta cell development; 2) Determine the precise molecular mechanism(s) underlying the intersection of RARa and GATA6 in the regulation gene expression pathways that promote pancreatic islet differentiation; and 3) Define how patient specific GATA6 disease mutations affect RA/GATA6 synergy and downstream pathways during pancreas development. The experiments proposed in this application will provide substantial novel insight into the conserved regulatory pathways that are required for appropriate pancreas development and islet cell differentiation and will further inform how mutations in GATA6 cause a wide range of pancreatic phenotypes in humans.


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 = $0 )
2025	2024	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	10/18/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $601,286 )
2024	2024	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	6	12/15/2023	NON-COMPETING CONTINUATION	$563,705
2024	2024	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	6	5/3/2024	NON-COMPETING CONTINUATION	$37,581
2024	2021	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	12/13/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $601,286

Issue Date FY: 2023 ( Subtotal = $645,153 )
2023	2023	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	12/15/2022	COMPETING CONTINUATION	$645,153
2023	2021	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	12/14/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $645,153

Issue Date FY: 2021 ( Subtotal = $532,409 )
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	4	4/26/2021	NON-COMPETING CONTINUATION	$532,409
														Subtotal = $532,409

Issue Date FY: 2020 ( Subtotal = $541,434 )
2020	2020	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	5/1/2020	NON-COMPETING CONTINUATION	$541,434
														Subtotal = $541,434

Issue Date FY: 2019 ( Subtotal = $542,556 )
2019	2019	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	4/26/2019	NON-COMPETING CONTINUATION	$542,556
														Subtotal = $542,556

Issue Date FY: 2018 ( Subtotal = $560,556 )
2018	2018	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	6/22/2018	NEW	$560,556
														Subtotal = $560,556

Grand Total All Awards = $3,423,394

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Intersection of signaling pathways and transcription factors regulating islet development

Award Number: R01DK118155

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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