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Control of epithelial morphology and bioenergetics by Toll receptors during dynamic tissue remodeling

Award Number: R01GM147372
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: 09/01/2023
PERIOD OF PERFORMANCE END DATE: 07/31/2028

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Control of epithelial morphology and bioenergetics by Toll receptors during dynamic tissue remodeling - Project Summary During development, epithelial cells undergo programmed changes in morphology and position to create complex tissues. Studies in model organisms have identified a conserved set of effector proteins that directly alter cell shape, although the upstream pathways that coordinate these processes across large groups of cells remain poorly understood. A paradigm for studying epithelial remodeling is cell intercalation in the Drosophila neurectoderm, and it was shown that three members of the highly conserved Toll receptor family are expressed in overlapping striped patterns to organize rapid cell rearrangements in this tissue. Toll receptors are widely expressed throughout human epithelia, and they have been extensively studied in the context of innate immune signaling. However, the control of cell morphology by Toll receptors has received very little attention. The focus of this proposal is to understand how non-uniform Toll receptor expression affects cortical tension, cell-cell adhesion, and mitochondrial dynamics to control cell shape and behavior during epithelial remodeling. We will use newly developed CRISPR/Cas9-derived genetic backgrounds and antibodies to characterize how Toll receptors control cell polarity to trigger intercalation; we will apply non-destructive techniques to characterize the bioenergetics of epithelial reorganization in intact living embryos; and we will investigate unaddressed links between Toll receptor, Rho, and G protein-coupled receptor signaling. Our first hypothesis is that neighboring cells sense differences in the expression of individual Toll receptor types to increase cortical tension and decrease cell-cell adhesion. We have developed a genetic system for expressing individual receptors in a single stripe that we will use to systematically characterize and compare the effects of each Toll receptor type on cell morphology and to identify the protein domains necessary for modulating cell shape. Our second hypothesis is that rapid cellular rearrangements during neurectoderm elongation require changes in mitochondrial signaling to drive cytoskeletal and junctional reorganization. To test this, we will use multiphoton microscopy to visualize the endogenous autofluorescence of metabolic cofactors to quantify cellular redox state in live embryos during epithelial remodeling, and then use gain- and loss-of-function techniques to determine what role mitochondrial fusion and fission play in epithelial reorganization. Our third hypothesis is that Toll receptor and GPCR signaling converge to activate Rho Kinase and trigger cell intercalation in the neurectoderm. We will use gain- and loss- of-functional analyses to determine how these two signaling pathways intersect to control cortical tension, cell- cell adhesion, and mitochondrial dynamics during epithelial remodeling. Successful completion of these experiments will give us a more comprehensive understanding of how Toll receptors function at a molecular level to control cellular biomechanics and bioenergetics during dynamic tissue remodeling.


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 = $311,171 )
2025	2025	UNIVERSITY OF ARKANSAS	1125 W MAPLE ST STE 316	FAYETTEVILLE	AR	72701	WASHINGTON	USA	Biomedical Research and Research Training	000	3	7/29/2025	NON-COMPETING CONTINUATION	$311,171
														Subtotal = $311,171

Issue Date FY: 2024 ( Subtotal = $311,353 )
2024	2024	UNIVERSITY OF ARKANSAS	1125 W MAPLE ST STE 316	FAYETTEVILLE	AR	72701	WASHINGTON	USA	Biomedical Research and Research Training	000	2	7/10/2024	NON-COMPETING CONTINUATION	$311,353
														Subtotal = $311,353

Issue Date FY: 2023 ( Subtotal = $311,527 )
2023	2023	UNIVERSITY OF ARKANSAS	1125 W MAPLE ST STE 316	FAYETTEVILLE	AR	72701	WASHINGTON	USA	Biomedical Research and Research Training	000	1	8/24/2023	NEW	$311,527
														Subtotal = $311,527

Grand Total All Awards = $934,051

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Control of epithelial morphology and bioenergetics by Toll receptors during dynamic tissue remodeling

Award Number: R01GM147372

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: 09/01/2023

PERIOD OF PERFORMANCE END DATE: 07/31/2028

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