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Intersection of the mTOR/p70S6K1 signaling and the HIPPO-Yap tissue organizer in neurulation and diabetic embryopathy

Award Number: R01HD108705
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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SUMMARY Pregestational diabetes induces neural tube defects (NTDs). There are 60 million women of reproductive age (18-44 years old) worldwide, and approximately 3 million American women with diabetes. Even under the best prenatal care, women with diabetes are still three- to four-times more likely to have a child with birth defects than women without diabetes. Unraveling the mechanism underlying diabetes-induced NTDs is critical for understanding its pathogenesis and providing potential intervention targets. Yes-associated protein (Yap), a transcriptional co-activator, determines body and organ size and regulates cell apoptosis, proliferation, and differentiation. We found that either conditional KO of Yap or transgenic (Tg) overexpression of constitutively active Yap (CA-Yap) specifically in the neuroepithelium resulted in NTD formation. Our recently published data demonstrate that one of the mTOR (mechanistic target of rapamycin) downstream kinase p70S6K1 is activated by maternal diabetes and its deficiency alleviates diabetic embryopathy. Furthermore, the mTOR inhibitor rapamycin prevents diabetic embryopathy. Both the HIPPO-Yap pathway and the mTOR pathway induce cell and tissue growth. Thus, we hypothesize that maternal diabetes activates mTOR-p70S6K1, which antagonizes Yap by activating the HIPPO kinase Lats1 through phosphorylation, selectively increases translation and disrupts endoplasmic reticulum (ER) homeostasis, leading to NTDs. Lats1 inactivates Yap through phosphorylation that disrupts the planar cell polarity (PCP) leading to failed neurulation. To test our hypothesis, we propose the following aims. Specific Aim 1. determine whether the major mTOR downstream effector p70S6K1 counteracts Yap activity by phosphorylating Yap upstream kinase Lats1 in diabetic embryopathy. We will examine whether maternal diabetes-activated the mTOR effector p70S6K1, which forms a tertiary complex with the scaffold protein Merlin and Lats1, triggers Lats1 phosphorylation in two previously unidentified sites, Thr255 and Thr262, leading to Yap inactivation. Specific Aim 2. To determine whether the HIPPO signaling kinase Lats1 activation leads to neural tube defects in diabetic embryopathy. We will test whether maternal diabetes induces Lats1 phosphorylation at new sites and subsequent the canonical phosphorylation sites which leads to suppression of Yap and NTD formation. Specific Aim 3. To investigate how fine-tuned Yap activity is critical for neurulation and its dysregulation disrupts planar cell polarity in diabetic embryopathy. We will assess that Yap activity is tightly controlled during neurulation and restoring Yap activity can ameliorate diabetic embryopathy. We will further evaluate whether fine-tuned Yap activity maintains PCP gene expression during neurulation.


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 = $586,642 )
2025	2025	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Child Health and Human Development Extramural Research	000	3	11/22/2024	NON-COMPETING CONTINUATION	$586,642
														Subtotal = $586,642

Issue Date FY: 2024 ( Subtotal = $645,307 )
2024	2024	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Child Health and Human Development Extramural Research	001	2	5/6/2024	NON-COMPETING CONTINUATION	$58,665
2024	2024	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Child Health and Human Development Extramural Research	000	2	11/14/2023	NON-COMPETING CONTINUATION	$586,642
														Subtotal = $645,307

Issue Date FY: 2023 ( Subtotal = $651,824 )
2023	2023	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Child Health and Human Development Extramural Research	000	1	12/21/2022	NEW	$651,824
														Subtotal = $651,824

Grand Total All Awards = $1,883,773

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Intersection of the mTOR/p70S6K1 signaling and the HIPPO-Yap tissue organizer in neurulation and diabetic embryopathy

Award Number: R01HD108705

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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