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Four-dimensional prediction and quantification of how physical forces impact organogenesis in zebrafish

Award Number: R01HD099031
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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PROJECT SUMMARY/ABSTRACT Defects in programmed cell shape changes during embryonic development can disrupt organ morphogenesis and cause structural birth defects. There are fundamental gaps in our understanding of how cells change their shape during organ formation. While the biochemical signals and morphogen gradients that help govern organogenesis are well-studied, evidence is growing that robust control of organ form and function often also depends on multiple mechanical mechanisms that remain poorly understood. Thus, there is a critical need to tease apart how multiple mechanisms – including tissue-scale dynamic forces and cell-autonomous contractile forces – work together to generate “mechanical gradients” that program cell and organ shape during organ formation. A challenge is that mechanical perturbations that affect the entire embryo often result in the same global phenotype, making it difficult to pinpoint the role of each mechanism. Our long- term goal is to develop a combined cell biology and modeling toolkit that allows us to predict cell-scale phenotypes and appropriate perturbations that can be used to distinguish between multiple mechanical mechanisms. This project uses Kupffer’s vesicle (KV), a transient epithelial organ that establishes left-right asymmetry in the zebrafish embryo, as a model system. No upstream biochemical signaling gradients have been identified that regulate KV cell shapes as required for left-right patterning, but multiple mechanical mechanisms have been implicated. Preliminary results – from (4D = 3D + time) experimental perturbations and measurements of single KV cell shapes, and novel mathematical models that simulate interacting 3D tissue structures while retaining cell-scale resolution – lead us to formulate our central hypothesis that cell shape changes critical for KV organogenesis result from mechanical gradients generated by interactions between the KV and surrounding tissue structures as well as cell-autonomous contractile forces from inside KV. The goal of Aim 1 is to determine how interactions between KV and notochord impact cell shape changes. 4D modeling predictions for cell shapes and cell movement combined with live in vivo imaging and localized laser ablations will determine how asymmetric forces generated by the rod-like notochord impact KV cell shape changes during organogenesis. The goal of Aim 2 is to understand mechanisms by which actomyosin contractility in surrounding tailbud cells and inside KV generate KV cell shape changes. Novel mathematical models will predict how localized optical perturbations to tailbud mechanics, as well as perturbations to volume and cell- autonomous contractility in cells inside the KV, affect KV organ shape. Key outputs include a modeling toolkit for high-throughput simulations of dynamic interactions between complex 3D tissue structures complemented by a cell biology toolkit that tests model predictions with spatially and temporally modulated activation of biomechanical and biochemical signaling molecules. These results will pinpoint mechanical mechanisms that regulate organogenesis, and may ultimately aid in the prediction or prevention of birth defects.


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 = $408,578 )
2024	2024	SYRACUSE UNIVERSITY	900 S CROUSE AVE	SYRACUSE	NY	13244	ONONDAGA	USA	Child Health and Human Development Extramural Research	000	5	8/19/2024	NON-COMPETING CONTINUATION	$408,578
														Subtotal = $408,578

Issue Date FY: 2023 ( Subtotal = $416,497 )
2023	2023	SYRACUSE UNIVERSITY	900 S CROUSE AVE	SYRACUSE	NY	13244	ONONDAGA	USA	Child Health and Human Development Extramural Research	000	4	8/28/2023	NON-COMPETING CONTINUATION	$416,497
														Subtotal = $416,497

Issue Date FY: 2022 ( Subtotal = $412,705 )
2022	2022	SYRACUSE UNIVERSITY	900 S CROUSE AVE STE 620	SYRACUSE	NY	13244	ONONDAGA	USA	Child Health and Human Development Extramural Research	000	3	8/26/2022	NON-COMPETING CONTINUATION	$412,705
														Subtotal = $412,705

Issue Date FY: 2021 ( Subtotal = $453,529 )
2021	2021	SYRACUSE UNIVERSITY	900 S CROUSE AVE STE 620	SYRACUSE	NY	13244	ONONDAGA	USA	Child Health and Human Development Extramural Research	000	2	8/18/2021	NON-COMPETING CONTINUATION	$453,529
														Subtotal = $453,529

Issue Date FY: 2020 ( Subtotal = $382,978 )
2020	2020	SYRACUSE UNIVERSITY	900 S CROUSE AVE STE 620	SYRACUSE	NY	13244	ONONDAGA	USA	Child Health and Human Development Extramural Research	000	1	9/25/2020	NEW	$382,978
														Subtotal = $382,978

Grand Total All Awards = $2,074,287

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Four-dimensional prediction and quantification of how physical forces impact organogenesis in zebrafish

Award Number: R01HD099031

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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