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Preeclampsia-Induced Fetal Endothelial Dysfunction in Obese Pregnancy: Novel roles of miR192-5p

Award Number: R03HD100778
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: 09/10/2020
PERIOD OF PERFORMANCE END DATE: 11/30/2022

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Preeclampsia-Induced Fetal Endothelial Dysfunction in Obese Pregnancy: Novel roles of miR192-5p - PROJECT SUMMARY / ABSTRACT Preeclampsia (PE) is a hypertensive disorder and one of the leading causes of fetal/maternal morbidity and mortality during pregnancy. PE is characterized by impaired fetal and maternal endothelial function and excessive inflammation. Children born to PE will face increased risks of cardiovascular disorders later in life, suggesting that PE programs fetal vascular cells in utero. To date, the mechanisms underlying PE-associated fetal endothelial dysfunction remain elusive. Maternal obesity is one of the prevalent risk factors that associated with PE in developed countries. Maternal obesity increases the overall risk of PE by 3 fold. Children born to obese mother also exhibit higher blood pressure and increased risks of adverse cardiovascular outcomes in adulthood. Elevated TNFα and TGFβ1 levels are associated with endothelial dysfunction in PE. Compared with lean subjects, obese women have increased pro-inflammatory cytokines (e.g. TNFα) levels in placenta and increased TGFβ1 levels in maternal circulation. Human umbilical vein is the blood vessel transporting all nutrition, O2, and other humoral factors (e.g. cytokines) from the placenta and maternal system into the fetus. Hence, human umbilical vein endothelial cells (HUVECs) is widely used as a human fetal endothelial cell model. MiR192- 5p is a cardiovascular diseases-associated microRNA which regulates endothelial cell growth in cultured HUVECs. Our preliminary data have shown that increased miR192-5p expression inhibits the TNFα- and TGFβ1-induced cell migration in HUVECs. We and others have reported that PE decreases miR192 expression in freshly isolated and unpassaged (P0)-HUVECs and in placentas. Our data further demonstrated that i) PE downregulated miR192-5p in male but not in female P0-HUVECs from lean pregnancies; ii) PE upregulated miR192-5p in both female and male P0-HUVECs from obese pregnancies; and iii) Male P1-HUVECs from lean PE exhibit weaker responses (monolayer integrity) to TNFα and TGF-β1 than female cells did. As TNFα and TGFβ1 are both upstream regulators of miR192- 5p, these data suggest that miR192-5p plays an important and differential role in TNFα and/or TGFβ1- regulated fetal endothelial function in lean and obese PE. Overall hypothesis: PE programs fetal endothelial cells by dysregulating endothelial function-associated microRNAs and their target genes, leading to fetal endothelial dysfunction, and ultimately laying the groundwork for adult onset cardiovascular disorders in children born to PE. Specifically, in this application, I will test the hypothesis that miR192-5p differentially regulates the PE-induced fetal endothelial dysfunction in lean and obese pregnancies via the TNFα and/or TGFβ1 signaling pathways using HUVECs as a model. Results from our proposed studies will advance our understanding of the roles of miRNAs in PE-induced fetal sex- specific endothelial dysfunction in lean and obese pregnancies. In the long term, these studies may reveal novel biomarkers or therapeutic targets for fetal sex-specific cardiovascular risk prediction, treatment, and even prevention in children born to lean and obese PE.


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 = $0 )
2024	2021	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Child Health and Human Development Extramural Research	000	2	10/13/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $76,750 )
2021	2021	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Child Health and Human Development Extramural Research	003	2	12/22/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$46,446
2021	2021	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Child Health and Human Development Extramural Research	001	2	12/7/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$76,750
2021	2020	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Child Health and Human Development Extramural Research	000	1	12/7/2020	NEW	$0
2021	2020	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Child Health and Human Development Extramural Research	002	1	12/22/2020	NEW	-$46,446
														Subtotal = $76,750

Issue Date FY: 2020 ( Subtotal = $77,500 )
2020	2020	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6401	MADISON	WI	53715	DANE	USA	Child Health and Human Development Extramural Research	000	1	12/11/2019	NEW	$77,500
														Subtotal = $77,500

Grand Total All Awards = $154,250

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Preeclampsia-Induced Fetal Endothelial Dysfunction in Obese Pregnancy: Novel roles of miR192-5p

Award Number: R03HD100778

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: 09/10/2020

PERIOD OF PERFORMANCE END DATE: 11/30/2022

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