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Comprehensive characterization of HNF1A-driven beta-cell heterogeneity

Award Number: R01DK113185
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: 07/01/2018
PERIOD OF PERFORMANCE END DATE: 06/30/2028

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Comprehensive characterization of HNF1A-driven beta-cell heterogeneity - PROJECT ABSTRACT The heterogeneity of pancreatic β-cells has been reported in many studies, but the field still lacks a consensus about its molecular signature and disease relevance. Our recent single cell multiome analysis suggested that HNF1A is a principal driver of a T2D-associated heterogeneity among the -cells from the same individual. By leveraging single cell Patch-seq data, we also discovered that HNF1A activity is associated with lower Na+ currents in β-cells and nominated a HNF1A target, FXYD2, as the primary mitigator. Since mutations in HNF1A are known to cause early onset diabetes (MODY3), there is a strong likelihood that HNF1A plays a causal role in T2D via governing -cell heterogeneity. In fact, many literatures studied HNF1A and its mutations due to the connection to MODY3, but little is known about its role in common diabetes in the context of -cell heterogeneity. It should be noted that although our previous work has demonstrated the power of single cell multiome to study -cell heterogeneity, the data did not allow us to directly compare the HNF1Ahi and HNF1Alo -cell populations due to technical difficulties. In this project we will develop new single cell multiome integration strategy to directly survey HNF1A function in -cell heterogeneity. We will establish stem cell models to manipulate HNF1A dosage in hESC-derived -cells, which will not only provide mechanistic insights into how HNF1A mediates MODY3 and -cell heterogeneity, but also offer new opportunity to improve the functionality of hPSC-derived -like cells for therapeutical benefits. We will also develop new cell line model to allow genetic and chemical screens for the upstream regulators of HNF1A in -cells. Taken together, our project will establish a new concept linking MODY3 gene HNF1A to common diabetes in the context of -cell heterogeneity.


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 = $597,761 )
2025	2025	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	7	6/24/2025	NON-COMPETING CONTINUATION	$597,761
2025	2022	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	2/12/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $597,761

Issue Date FY: 2024 ( Subtotal = $597,761 )
2024	2024	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	6/21/2024	COMPETING CONTINUATION	$597,761
														Subtotal = $597,761

Issue Date FY: 2022 ( Subtotal = $442,685 )
2022	2022	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	5/6/2022	NON-COMPETING CONTINUATION	$442,685
														Subtotal = $442,685

Issue Date FY: 2021 ( Subtotal = $442,685 )
2021	2021	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	4/30/2021	NON-COMPETING CONTINUATION	$442,685
														Subtotal = $442,685

Issue Date FY: 2020 ( Subtotal = $442,248 )
2020	2020	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	5/5/2020	NON-COMPETING CONTINUATION	$442,248
														Subtotal = $442,248

Issue Date FY: 2019 ( Subtotal = $443,006 )
2019	2019	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	4/4/2019	NON-COMPETING CONTINUATION	$443,006
2019	2018	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	2/28/2019	NEW	$0
														Subtotal = $443,006

Issue Date FY: 2018 ( Subtotal = $452,115 )
2018	2018	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	6/13/2018	NEW	$452,115
														Subtotal = $452,115

Grand Total All Awards = $3,418,261

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Comprehensive characterization of HNF1A-driven beta-cell heterogeneity

Award Number: R01DK113185

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: 07/01/2018

PERIOD OF PERFORMANCE END DATE: 06/30/2028

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