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Engineering Tools for Rapid Loss of Protein Function with Spatio-Temporal Control in Zebrafish

Award Number: R21HD110690
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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Engineering Tools for Rapid Loss of Protein Function with Spatio-Temporal Control in Zebrafish - PROJECT SUMMARY In zebrafish, the genetic toolkit is limited to global and tissue-specific gene inactivation. However, often it is desirable to inactivate genes in specific tissues and at specific times. Moreover, phenotypes do not become evident until pre-existing protein product from the targeted gene has decayed. This lag can be many hours or even days. This is a problem when studying rapid biological processes or genes that are required for cell survival. In recent years, several strategies have been developed to overcome these limitations. Most of the strategies target the protein gene product directly, typically by tagging the protein with a degron that can be induced to degrade the tagged protein. We recently adapted the deGradFP system from flies to zebrafish and called it zGrad. zGrad targets GFP-tagged proteins for degradation and reveals loss-of-function phenotypes. zGrad consists of a fusion of an anti-GFP nanobody to a F-box domain. zGrad binds GFP-tagged proteins through its anti-GFP nanobody part and targets the tagged protein to the E3 ubiquitin ligase complex for degradation through its F-box domain. In its current form, zGrad can be used to degrade proteins with either spatial or temporal control, but not both. Here we propose to engineer significant improvements to the zGrad system. Specifically, we will (1) expand zGrad so that it can be used to degrade proteins with combined spatial and temporal control, and (2) engineer zGrad so that it is regulated through light to induce degradation in specific cells and subcellular compartments at desired times. These improvements will make zGrad an extremely powerful and versatile system for inactivating genes rapidly in specific cells at specific times in zebrafish, and would provide proof-of-principle that the deGradFP/zGrad method could be adapted to function in any system.


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 = $254,250 )
2024	2024	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Child Health and Human Development Extramural Research	000	2	8/6/2024	NON-COMPETING CONTINUATION	$254,250
														Subtotal = $254,250

Issue Date FY: 2023 ( Subtotal = $211,875 )
2023	2023	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Child Health and Human Development Extramural Research	000	1	3/21/2023	NEW	$211,875
														Subtotal = $211,875

Grand Total All Awards = $466,125

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Engineering Tools for Rapid Loss of Protein Function with Spatio-Temporal Control in Zebrafish

Award Number: R21HD110690

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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