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Reverse Engineering the Extracellular Neighborhood to Support the Functional Tissue Unit: A Use Case to Restore Ovarian Function

Award Number: U01HD110336
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/24/2022
PERIOD OF PERFORMANCE END DATE: 07/31/2026

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Reverse Engineering the Extracellular Neighborhood to Support the Functional Tissue Unit: A Use Case to Restore Ovarian Function - PROJECT SUMMARY/ABSTRACT Static human biomolecular atlases miss dimensionality that is critical for establishing the healthy condition. We are uniquely positioned with rare resources and expertise to fill in these dimensions and enhance the healthy human ovary HuBMAP data. Here, we will contribute the developmental dimension by defining the change in interstitial cells across the pubertal transition; we will create the spatial dimension by probing the biochemical and physical cues of the extracellular matrix (ECM) across anatomical compartments and functional cell unit neighborhoods, and we will create the temporal dimension by investigating the changes in functional cell units during ooplasm maturation and hormone production. Without these added dimensions, the HuBMAP datasets are less effective in identifying and understanding disease modalities. Our long-term goal is to increase the utility of the ovary atlas using existing and new datasets to inform regenerative medicine technologies that improve the safety, efficacy and longevity of fertility and hormone restoration options for patients with premature ovarian insufficiency (POI), a disease that occurs in approximately 1% of women in the USA. Individuals with POI have a reduced quality of life and life expectancy of ~ 2 years shorter from comorbidities that include cognitive and cardiovascular diseases. We will incorporate data from the University of Pennsylvania (UPENN) HuBMAP Tissue Mapping Center (TMC) and the University of Michigan (UM) Chan Zuckerberg Initiative Human Cell Atlas (HCA) multiome maps of healthy adult ovaries. The Vanderbilt University Biomolecular Multimodal Imaging Center (BIOMIC) developed imaging and biocomputational analysis pipelines that enable 3D multimodel reconstruction and molecular profiling. Additionally, we have generated ECM and associated protein maps on model and human ovaries, in collaboration with the Northwestern University (NU) HuBMAP Rapid Technology Implementation (RTI) center. Finally, we have developed engineering tools, such as scaffolds that support ovarian follicles and protocols to make ovarian hormone-producing cells from human induced pluripotent stem cells (iPSCs). These resources and collaborations will provide valuable tissue and functional unit insights and, combined with our expertise in tissue engineering, will enable us to reverse engineer the extracellular neighborhood that supports ovarian follicle growth to improve fertility and hormone restoration options. We will (1) add developmental and spatial dimensions to the human ovary atlas to identify changes in the neighborhood that impact folliculogenesis, (2) demonstrate the utility of the HuBMAP data and tools to address important biological questions within the ovary and reverse engineer a neighborhood that supports follicle growth, and (3) reverse engineer a personalized ovarian hormone-replacement therapy from human iPSCs by defining and validating the response of cells to ECM environments. By achieving these milestones, we will add to the functionality of the HuBMAP ovary atlas, demonstrate the utility of these datasets, and develop pipelines and technologies for future regenerative technologies that may be developed from other HuBMAP tissue atlases.


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	ANN & ROBERT H LURIE CHILDRENS HOSPITAL OF CHICAGO	225 E CHICAGO AVE	CHICAGO	IL	60611	COOK	USA	Child Health and Human Development Extramural Research	000	3	5/14/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $390,806 )
2024	2024	ANN & ROBERT H LURIE CHILDRENS HOSPITAL OF CHICAGO	225 E CHICAGO AVE	CHICAGO	IL	60611	COOK	USA	Child Health and Human Development Extramural Research	001	3	8/15/2024	NON-COMPETING CONTINUATION	$390,806
2024	2023	ANN & ROBERT H LURIE CHILDRENS HOSPITAL OF CHICAGO	225 E CHICAGO AVE	CHICAGO	IL	60611	COOK	USA	Child Health and Human Development Extramural Research	000	2	8/9/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $390,806

Issue Date FY: 2023 ( Subtotal = $551,979 )
2023	2023	ANN & ROBERT H LURIE CHILDRENS HOSPITAL OF CHICAGO	225 E CHICAGO AVE	CHICAGO	IL	60611	COOK	USA	Child Health and Human Development Extramural Research	000	2	7/11/2023	NON-COMPETING CONTINUATION	$401,979
2023	2023	ANN & ROBERT H LURIE CHILDRENS HOSPITAL OF CHICAGO	225 E CHICAGO AVE	CHICAGO	IL	60611	COOK	USA	Child Health and Human Development Extramural Research	001	2	7/25/2023	SUPPLEMENT FOR EXPANSION	$150,000
														Subtotal = $551,979

Issue Date FY: 2022 ( Subtotal = $423,231 )
2022	2022	ANN & ROBERT H LURIE CHILDRENS HOSPITAL OF CHICAGO	225 E CHICAGO AVE	CHICAGO	IL	60611	COOK	USA	Child Health and Human Development Extramural Research	000	1	8/24/2022	NEW	$423,231
														Subtotal = $423,231

Grand Total All Awards = $1,366,016

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Reverse Engineering the Extracellular Neighborhood to Support the Functional Tissue Unit: A Use Case to Restore Ovarian Function

Award Number: U01HD110336

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/24/2022

PERIOD OF PERFORMANCE END DATE: 07/31/2026

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