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THE ROLE OF MESENCHYMAL PROGENITOR CELLS IN ABNORMAL UTERINE REPAIR

Award Number: R01HD109326
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/15/2023
PERIOD OF PERFORMANCE END DATE: 03/31/2025

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THE ROLE OF MESENCHYMAL PROGENITOR CELLS IN ABNORMAL UTERINE REPAIR - PROJECT SUMMARY Dilation & curettage (D&C) is one of the most common surgical procedures performed on women throughout the world. Intrauterine adhesions (iUA), or Asherman, develop in about 40% of women who undergo D&C in the postpartum (6 week period after birth), but is very rare after D&C in nonpregnant women (<1%) for reasons that are not well understood. It is a debilitating condition characterized by intrauterine fibrosis and scarring. Patients with iUA suffer from infertility, recurrent pregnancy loss and a broad range of dangerous pregnancy complications (e.g. preterm birth). While endometrial mesenchymal stem/progenitor cells (eMPCs) are crucial for endometrial repair, the role of these cells and underlying molecular mechanisms in this postpartum susceptibility of the endometrium to fibrosis and abnormal repair are unknown. This application is specifically focused on defining the role that eMPCs and their stromal fibroblast progeny play in abnormal uterine repair. The central hypothesis is that eMPCs of the recently postpartum uterus are more senescent and inherently different in their response to uterine injury compared to eMPCs of the nonpregnant uterus, leading to fibrosis and scar formation. The approach is to use our novel postpartum mouse uterine injury model which recapitulates the susceptibility of the human postpartum uterus to injury. Using it, we will define the dynamic changes in eMPCs and their differential response to uterine injury in the postpartum vs. nonpregnant, identify using lineage tracing the eMPC subsets that become the profibrotic fibroblast cells, and conditionally ablate each of these eMPC subsets to define their functional role in endometrial fibrosis (Aim 1). We will obtain fresh human endometrial tissue from women undergoing postpartum D&C and compare it to nonpregnant tissue using innovative single cell technology and functional in vitro studies to gain detailed insights into the cellular and molecular differences that predispose the human endometrium to form iUA (Aim 2). In Aim 3, we will obtain archived endometrial specimens from the time of inciting D&C event from women who developed Asherman vs. non-Asherman. We will use the innovative deterministic barcoding in tissue spatial multi-omics sequencing (DBiT-seq) platform and integrate it with immunofluorescence to gain detailed molecular insights regarding eMPCs and their cell interactions within the tissue, identifying novel therapeutic targets for iUA prevention. The proposed aims are conceptually and technically innovative and together will have a broad impact on the field by filling a substantial gap in our fundamental knowledge of endometrial biology and infertility pathogenesis using Omics approach, which are major research priorities of the Fertility and Infertility Branch of the NICHD. Ultimately, the knowledge gained from this proposal will not only be invaluable to our understanding of many more subtle conditions of abnormal endometrial repair, but provide unique insights into the body’s physiological anti-fibrotic wound healing mechanisms leading to a deeper understanding of the pathogenesis of fatal idiopathic fibrotic diseases in other organs.


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 = $576,294 )
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Child Health and Human Development Extramural Research	000	3	4/3/2025	NON-COMPETING CONTINUATION	$576,294
2025	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Child Health and Human Development Extramural Research	001	2	4/25/2025	TERMINATION	$0
														Subtotal = $576,294

Issue Date FY: 2024 ( Subtotal = $757,348 )
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Child Health and Human Development Extramural Research	001	2	5/3/2024	NON-COMPETING CONTINUATION	$568,392
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Child Health and Human Development Extramural Research	002	2	5/6/2024	SUPPLEMENT FOR EXPANSION	$146,764
2024	2024	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Child Health and Human Development Extramural Research	000	1	1/17/2024	SUPPLEMENT FOR EXPANSION	$42,192
														Subtotal = $757,348

Issue Date FY: 2023 ( Subtotal = $550,775 )
2023	2023	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Child Health and Human Development Extramural Research	000	1	5/15/2023	NEW	$550,775
														Subtotal = $550,775

Grand Total All Awards = $1,884,417

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THE ROLE OF MESENCHYMAL PROGENITOR CELLS IN ABNORMAL UTERINE REPAIR

Award Number: R01HD109326

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/15/2023

PERIOD OF PERFORMANCE END DATE: 03/31/2025

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