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Revealing LIM-Domain Transcriptional Complexes that Establish and Maintain Alpha-Cell Mass

Award Number: R01DK111483
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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Revealing LIM-Domain Transcriptional Complexes that Establish and Maintain Alpha-Cell Mass - PROJECT SUMMARY/ABSTRACT Pancreatic islets of Langerhans contain insulin-secreting β-cells and glucagon-producing α-cells that function in concert to maintain glucose homeostasis. Dysfunction in islet activity, cell identity, or survival results in diabetes mellitus, a disease affecting millions of Americans with numbers expected to greatly increase. It is known that dysregulated α-cells are also major contributors to type 1 and type 2 diabetes, yet the research focus for decades has largely been on the β-cell. Thus, the key regulators driving α-cell development and adult function are much less defined than in β-cells. Increased knowledge of the effectors of embryonic α-cell development will be instructive for generating ES cell-derived α-cells for islet replacement therapies, while a greater understanding of adult α-cell functional identity will help us understand how the α-cell responds to glucose dysregulation, likely providing novel therapeutic strategies. We and others previously demonstrated that the Islet-1 transcription factor is required for mouse β-cell development and function and has human gene variants that are strongly linked to islet function and diabetes. In addition, transcriptional control imposed by Islet-1 in β-cells requires the interacting co-regulator, LDB1, with strong evidence for Islet-1:LDB1 complex activity also in α-cells. However, nothing is known of the mouse or human α-cell target genes and pathways governed by these factors. Interestingly, the complexity of LDB1- mediated transcriptional control is also greater than simply through Islet-1, potentially involving other islet- enriched transcription factors including GATA6 and/or NEUROD1. These observations support that LDB1 may mediate multiple distinct α-cell complexes to elicit transcriptional and functional impacts. Three complementary Aims will define comparative roles of Islet-1 and LDB1 during embryonic mouse development and adult mouse and human α-cell function. Preliminary embryonic knockout model data suggests that α-cell Islet-1 and LDB1 are each required to maintain postnatal glucose homeostasis. We will further explore the impacts of α-cell-specific Islet-1 or LDB1 deficiency in developing and postnatal mice, and in donor human islets. This proposal will test the hypothesis that Ldb1-mediated complexes comprise a central node to regulate transcription in multiple phases of mammalian α-cell development and postnatal function, through Islet-1 and potentially other islet transcription factors. Our extensive experience studying transcription factor complexes and readily-available in vitro and in vivo reagents, make us uniquely suited for executing these Aims. Results reported from this proposal will benefit efforts in developing new molecular targets and cell-based therapies to combat 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: 2025 ( Subtotal = $660,856 )
2025	2025	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	3901 RAINBOW BLVD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	4/2/2025	COMPETING CONTINUATION	$660,856
														Subtotal = $660,856

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	1/17/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $371,250 )
2021	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	4/30/2021	NON-COMPETING CONTINUATION	$371,250
														Subtotal = $371,250

Issue Date FY: 2020 ( Subtotal = $371,250 )
2020	2020	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	5/8/2020	NON-COMPETING CONTINUATION	$371,250
														Subtotal = $371,250

Issue Date FY: 2019 ( Subtotal = $371,250 )
2019	2019	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	4/26/2019	NON-COMPETING CONTINUATION	$371,250
														Subtotal = $371,250

Issue Date FY: 2018 ( Subtotal = $371,250 )
2018	2018	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	5/7/2018	NON-COMPETING CONTINUATION	$371,250
														Subtotal = $371,250

Issue Date FY: 2017 ( Subtotal = $371,250 )
2017	2017	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	6/8/2017	NEW	$371,250
														Subtotal = $371,250

Grand Total All Awards = $2,517,106

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Revealing LIM-Domain Transcriptional Complexes that Establish and Maintain Alpha-Cell Mass

Award Number: R01DK111483

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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