Monday, October 6, 2025 10/6/2025

Linking Hedgehog and Nodal/TGF-beta signaling in the establishment of left-right asymmetry

Award Number: R01GM147160
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/22/2022
PERIOD OF PERFORMANCE END DATE: 07/31/2026

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Linking Hedgehog and Nodal/TGF-beta signaling in the establishment of left-right asymmetry - Project summary/abstract The establishment of left-right (LR) asymmetry is a critical event required for the correct positioning of internal organs. Defects in human LR axis formation cause birth defects of the heart, vasculature, lungs, and intestinal tract. The gene network contributing to the generation of LR asymmetry is highly conserved across vertebrates. In the mouse, the initial asymmetric signals establishing LR axis are determined in the node by cilia-driven leftward fluid flow (nodal flow). These signals are then transferred to the left lateral plate mesoderm (LPM), which will undergo asymmetric organ morphogenesis. Nodal, a secretory protein that belongs to the transforming growth factor-b (TGF-b) superfamily, is expressed in the node and travels a long distance to the left LPM, where it initiates a transient auto-regulatory circuit (involving Nodal and Lefty) that propagates Nodal signaling and activates expression of the left-sided determinant Paired-Like Homeodomain transcription factor 2 (Pitx2). The Hedgehog (Hh) signaling pathway also plays a crucial role in LR patterning. In the mouse, Hh signaling is required to establish the midline that separates the left and right sides of the embryo, as well as to activate the Nodal-dependent auto-regulatory circuit in the LPM. However, the mechanism by which Hh signaling regulates the competence of the LPM for Nodal response is not well understood. Thus, identifying the specific convergence point of the Hh and TGF-b pathways is critical for understanding the in-depth mechanism underlying LR asymmetry determination, and therefore to provide better diagnosis, preventive and therapeutic intervention against LR asymmetry-related birth defects. We recently found that a novel target of the Hh pathway, Neuron-Derived Neurotrophic Factor (Ndnf), regulates axial rotation and intestinal looping in the mouse. In the proposed work, we will incorporate biochemical, molecular, and genetic approaches to (Aim 1) assess the source, (Aim 2) determine the transcriptional regulation, and (Aim 3) investigate the underlying molecular mechanisms of Ndnf in LR determination.


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 = $361,461 )
2025	2025	GEORGE WASHINGTON UNIVERSITY (THE)	1918 F ST NW	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	Biomedical Research and Research Training	000	4	7/28/2025	NON-COMPETING CONTINUATION	$323,000
2025	2025	GEORGE WASHINGTON UNIVERSITY (THE)	1918 F ST NW	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	Biomedical Research and Research Training	001	4	8/7/2025	SUPPLEMENT FOR EXPANSION	$38,461
														Subtotal = $361,461

Issue Date FY: 2024 ( Subtotal = $399,921 )
2024	2024	GEORGE WASHINGTON UNIVERSITY (THE)	1918 F ST NW	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	Biomedical Research and Research Training	000	2	5/9/2024	SUPPLEMENT FOR EXPANSION	$19,230
2024	2024	GEORGE WASHINGTON UNIVERSITY (THE)	1918 F ST NW	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	Biomedical Research and Research Training	002	3	7/31/2024	SUPPLEMENT FOR EXPANSION	$57,691
2024	2024	GEORGE WASHINGTON UNIVERSITY (THE)	1918 F ST NW	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	Biomedical Research and Research Training	001	3	7/30/2024	NON-COMPETING CONTINUATION	$323,000
														Subtotal = $399,921

Issue Date FY: 2023 ( Subtotal = $323,000 )
2023	2023	GEORGE WASHINGTON UNIVERSITY (THE)	1918 F ST NW	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	Biomedical Research and Research Training	000	2	7/28/2023	NON-COMPETING CONTINUATION	$323,000
														Subtotal = $323,000

Issue Date FY: 2022 ( Subtotal = $304,866 )
2022	2022	GEORGE WASHINGTON UNIVERSITY, THE	1918 F ST NW	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	Biomedical Research and Research Training	000	1	9/22/2022	NEW	$304,866
														Subtotal = $304,866

Grand Total All Awards = $1,389,248

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Linking Hedgehog and Nodal/TGF-beta signaling in the establishment of left-right asymmetry

Award Number: R01GM147160

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/22/2022

PERIOD OF PERFORMANCE END DATE: 07/31/2026

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