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Defining the link between trisomy 21 and placentation defects

Award Number: F32HD116568
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: 12/01/2024
PERIOD OF PERFORMANCE END DATE: 11/30/2027

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Defining the link between trisomy 21 and placentation defects - Down’s Syndrome (T21) is the most common aneuploidy disorder in humans. T21 pregnancies are at an increased risk of adverse pregnancy outcomes including stillbirth and intrauterine growth restriction resulting from placental insufficiency. T21 is also accompanied by comorbidities including congenital heart disease, also linked to inadequate placentation. Coincidentally, T21 placental syncytiotrophoblasts that act as the primary barriers at the maternal-fetal interface fail to adequately fuse into multinucleated syncytial plaques, and the underlying etiology is unknown. We hypothesize that defects in T21 syncytiotrophoblast differentiation occur during peri-implantation development and contribute to a wide range of diseases in individuals with T21. The long-term goals of our research are to provide a mechanism by which syncytiotrophoblast differentiation is disrupted in T21 and provide opportunities for therapeutic intervention. In Aim 1, we will identify transcriptional differences of T21 implantation-stage trophoblasts by differentiating six pairs of T21 and matching euploid induced pluripotent stem (iPS) cell lines into syncytiotrophoblast-like cells with treatment of BMP4, A83-01, and PD173074 (BAP) and performing RNA-sequencing. In Aim 2, we will assess canonical estrogen-driven transcription in T21 and euploid BAP-treated iPS cells. We will knockdown the third copy of NRIP1, an estrogen receptor inhibitor on chromosome 21, with CRISPR/Cas9 technology in T21 BAP-treated iPS cells to determine the influence of estrogen receptor inhibition on T21 syncytiotrophoblast fusion. We will also overexpress a third copy of NRIP1 in euploid lines and measure estrogen mediated transcriptional activity and syncytiotrophoblast cell fusion. These results will help to confirm or deny the involvement of NRIP1 and canonical estrogen signaling in the T21 syncytiotrophoblast disease phenotype. In Aim 3, we will differentiate T21 and euploid iPSCs to cardiomyocytes and supplement them with conditioned medium from T21 and euploid trophoblast cultures to reveal a relationship between impaired T21 trophoblasts on cardiomyocyte development. In summary, our proposal uses cutting edge models and techniques that have not been used in T21 trophoblast research to demonstrate the significance of abnormal placentation on long-term health.


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 = $78,052 )
2026	2026	THE REGENTS OF THE UNIVERSITY OF COLORADO	3100 MARINE ST	BOULDER	CO	80309	BOULDER	USA	Child Health and Human Development Extramural Research	000	2	1/12/2026	NON-COMPETING CONTINUATION	$78,052
														Subtotal = $78,052

Issue Date FY: 2024 ( Subtotal = $76,408 )
2024	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	3100 MARINE ST	BOULDER	CO	80309	BOULDER	USA	Child Health and Human Development Extramural Research	000	1	7/26/2024	NEW	$76,408
2024	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	3100 MARINE ST	BOULDER	CO	80309	BOULDER	USA	Child Health and Human Development Extramural Research	001	1	7/26/2024	NEW	$0
														Subtotal = $76,408

Grand Total All Awards = $154,460

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Defining the link between trisomy 21 and placentation defects

Award Number: F32HD116568

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: 12/01/2024

PERIOD OF PERFORMANCE END DATE: 11/30/2027

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