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A HUMAN IPSC-BASED ORGANOID PLATFORM FOR STUDYING MATERNAL HYPERGLYCEMIA-INDUCED CONGENITAL HEART DEFECTS

Award Number: F31HD113330
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 02/01/2024
PERIOD OF PERFORMANCE END DATE: 01/31/2029

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A HUMAN IPSC-BASED ORGANOID PLATFORM FOR STUDYING MATERNAL HYPERGLYCEMIA-INDUCED CONGENITAL HEART DEFECTS - Congenital heart defects (CHD) are the most common type of birth defect, with cardiac malformation resulting from abnormal heat development contributed by genetic and/or environmental risk factors. The association of maternal diabetes with increased offspring CHD incidence is proposed to be attributed to factors including glucose imbalance and metabolic dysregulation. Murine studies on hyperglycemia have been beneficial in uncovering the phenotypic effects of maternal hyperglycemia on embryonic development, with reports that high glucose conditions are associated with general suppression of WNT signaling, apoptosis, and excessive reactive oxygen species (ROS) production. However, little is known about the effects of hyperglycemia on human stem cells in regard to cardiomyocyte determination, metabolism, and functionality. Additionally, there is little reports of these alterations using induced pluripotent stemcells (iPSCs), which provide an opportunityto observe cardiac progenitor cell (CPC) heterogeneity, multicellular crosstalk, and differentiated cell functionality at key development timepoints. We hypothesize that high glucose environments interfere with normal cardiac differentiation to cause altered cell lineage determination in iPSCs and iPSC-derived cardiomyocytes (iPSC- CMs). We propose use of immunofluorescence assays and staining to quantify mitochondrial metabolism, mitochondrial ROS production, and apoptosis marker amounts. Our goal is to investigate the impact of high glucose on human cardiomyocyte differentiation and crosstalk signaling abnormalities during 3D stem cell differentiation that could lead to impaired cardiac development. We will investigate differentially expressed genes at the single-cell resolutionin early and late differentiation in responseto high glucose doses in iPSC populations. Should our transcriptional profiling comparisons yield iPSC and iPSC-CM expression differences, the resulting phenotypes would provide insight into cardiac cell determination during hyperglycemic conditions. Understanding the hyperglycemia-response mechanisms is important in the onset of maternal hyperglycemia- associated CHD. These mechanisms would be further investigated through looking at cell lineage population composition in organoids and analyze response per lineage to narrow down what structures of the mature heart are affected.


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: 2026 ( Subtotal = $43,714 )
2026	2026	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Child Health and Human Development Extramural Research	000	3	1/22/2026	NON-COMPETING CONTINUATION	$43,138
2026	2026	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Child Health and Human Development Extramural Research	001	3	4/1/2026	NON-COMPETING CONTINUATION	$576
														Subtotal = $43,714

Issue Date FY: 2025 ( Subtotal = $43,138 )
2025	2025	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Child Health and Human Development Extramural Research	000	2	1/16/2025	NON-COMPETING CONTINUATION	$42,574
2025	2025	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Child Health and Human Development Extramural Research	001	2	7/30/2025	NON-COMPETING CONTINUATION	$564
														Subtotal = $43,138

Issue Date FY: 2023 ( Subtotal = $41,294 )
2023	2023	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Child Health and Human Development Extramural Research	000	1	8/16/2023	NEW	$41,294
2023	2023	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Child Health and Human Development Extramural Research	001	1	9/21/2023	NEW	$0
														Subtotal = $41,294

Grand Total All Awards = $128,146

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A HUMAN IPSC-BASED ORGANOID PLATFORM FOR STUDYING MATERNAL HYPERGLYCEMIA-INDUCED CONGENITAL HEART DEFECTS

Award Number: F31HD113330

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 02/01/2024

PERIOD OF PERFORMANCE END DATE: 01/31/2029

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