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Intercellular interactions define cell migrations and transitions that maintain fetal membrane homeostasis

Award Number: R01HD100729
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

Group Awards By Issue Date FY or Funding FY:

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Fetal membranes (amniochorion) protect the fetus during pregnancy. At term, senescence (aging) and inflammation cause functional and mechanical instability to membrane cells, contributing to parturition. Premature senescence and membrane dysfunctions are associated with preterm birth (PTB) and preterm premature rupture of the membranes (pPROM). However, cellular-level changes contributing to membrane stability during gestation and its dysfunction leading to labor and delivery are still unclear. Recent studies of senescent term and preterm membranes revealed “microfractures” (MFs), sites of cellular remodeling. MFs are resealed during gestation to maintain membrane integrity. Higher numbers of MFs and their increased morphometry (depth and width) in term labor, pPROM, and PTB membranes compared to respective controls suggest MFs' resealing is compromised. Amnion epithelial cells in MFs have been observed undergoing epithelial mesenchymal transition (EMT). Further, these cells showed proliferative and resealing properties of deepithelialized (nude/cell free) areas to stabilize membranes. At the healing edge of MFs, amnion mesenchymal cells exhibited a reverse phenomenon, mesenchymal-epithelial transition (MET). From these findings, we postulate that cellular transitions are essential for maintaining fetal membrane integrity. We hypothesize that MFs are areas of membrane remodeling and their increased number and morphometry are associated with failure to remodel and dysfunctional membranes. Understanding intercellular and cell-matrix interactions causing MFs' development and their resealing will help us to determine how oxidative stress (OS) and inflammation can contribute to the persistence of MFs and dysfunctional membrane status in PTB and pPROM. Two specific aims to be tested are Specific Aim 1: To investigate the dynamic remodeling of the fetal membrane epithelium in an in vitro model of cell-free (nude) membranes during OS and infection / inflammation compared to normal conditions; Specific Aim 2: To determine cell migration, matrix degradation, and cellular transition associated with MFs' formation using a fetal membrane organ-on-a-chip approach. This multidisciplinary proposal combines cell and molecular biological and bioengineering approaches designed to overcome the limitations of classic 2D cell cultures by developing a fetal membrane-on-a-chip using organ-on-chip technologies. This model system will maintain multiple cell types in close proximity with constant dynamic interactions, similar to the conditions in utero. We will elucidate causative molecular mechanisms of (normal and abnormal) biologic MFs' formation and how they contribute to PTB and pPROM. Understanding cellular-level mechanisms will allow us to design strategies to minimize MFs' development to strengthen intrauterine cavities and reduce the risk of PTB and pPROM.


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: 2024 ( Subtotal = $395,940 )
2024	2024	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Child Health and Human Development Extramural Research	000	5	2/6/2024	NON-COMPETING CONTINUATION	$395,940
														Subtotal = $395,940

Issue Date FY: 2023 ( Subtotal = $439,932 )
2023	2023	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Child Health and Human Development Extramural Research	000	4	2/28/2023	NON-COMPETING CONTINUATION	$439,932
														Subtotal = $439,932

Issue Date FY: 2022 ( Subtotal = $439,932 )
2022	2022	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Child Health and Human Development Extramural Research	000	3	2/14/2022	NON-COMPETING CONTINUATION	$395,935
2022	2022	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Child Health and Human Development Extramural Research	001	3	4/29/2022	NON-COMPETING CONTINUATION	$43,997
														Subtotal = $439,932

Issue Date FY: 2021 ( Subtotal = $444,593 )
2021	2021	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Child Health and Human Development Extramural Research	000	2	2/19/2021	NON-COMPETING CONTINUATION	$444,593
2021	2021	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Child Health and Human Development Extramural Research	001	2	4/1/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $444,593

Issue Date FY: 2020 ( Subtotal = $833,434 )
2020	2020	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Child Health and Human Development Extramural Research	001	1	9/4/2020	SUPPLEMENT FOR EXPANSION	$280,934
2020	2020	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Child Health and Human Development Extramural Research	000	1	3/12/2020	NEW	$552,500
														Subtotal = $833,434

Grand Total All Awards = $2,553,831

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Intercellular interactions define cell migrations and transitions that maintain fetal membrane homeostasis

Award Number: R01HD100729

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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