Tuesday, August 19, 2025 8/19/2025

Combining protein and DNA engineering to create bioswitches

Award Number: R01GM148448
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: 09/20/2022
PERIOD OF PERFORMANCE END DATE: 08/31/2026

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Combining protein and DNA engineering to create bioswitches - Project Summary and Relevance The goal of this project is to develop mechanisms by which ordinary proteins can be turned into ligand- activated conformational switches. When naturally-occurring proteins of this type are discovered, their engineering can result in technologies that transform biology. For example, CRISPR-associated protein catalytic activity is switched on by binding of guide RNA, and calmodulin undergoes a large conformational change upon ligating calcium. Developing these proteins into DNA manipulation tools and fluorescent calcium sensors, respectively have revolutionized gene editing and the study of calcium signaling. The current proposal asks the question, “what else is possible if other proteins and enzymes can be made to switch on/off by binding of DNA, RNA, or other ligands?”. The proposed project takes a combined biophysical, computational, and cellular approach to develop a general mechanism for linking protein function to ligand binding. Three families of protein switches will be created. The first is a biosensor that plugs into existing DNA tools (such as aptamers and toehold-mediated strand displacement hairpins) without any modification to the sensor, to detect a DNA or RNA sequence of choice. The output is ratiometric (blue/green) luminescence that can be detected by cell phone camera. The second family employs fibronectin 3 ‘monobodies’ as the input domains and fluorescent proteins as the output domains to provide a ratiometric FRET response, or large increase in fluorescence intensity, when encountering an intracellular target. In the third switch design, the enzymatic activity of a bacterial RNase is turned on by cytomegalovirus (CMV) RNA to kill CMV-infected human cells. This last aim addresses the pressing need of preventing transplant-related CMV disease. Relevance. This study will open the biological activity of the human proteome to potential regulation by binding of nucleic acids, proteins, and small molecules. The modular design allows mixing and matching of different proteins to generate molecules with functionalities not found in nature. Examples include biosensors for pathogens and disease biomarkers, and an enzyme that kills virally-infected human cells while leaving uninfected cells unharmed.


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 = $336,776 )
2025	2025	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	750 E ADAMS ST	SYRACUSE	NY	13210	ONONDAGA	USA	Biomedical Research and Research Training	000	4	8/12/2025	NON-COMPETING CONTINUATION	$336,776
														Subtotal = $336,776

Issue Date FY: 2024 ( Subtotal = $448,125 )
2024	2024	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	750 E ADAMS ST	SYRACUSE	NY	13210	ONONDAGA	USA	Biomedical Research and Research Training	001	3	8/27/2024	NON-COMPETING CONTINUATION	$360,610
2024	2024	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	750 E ADAMS ST	SYRACUSE	NY	13210	ONONDAGA	USA	Biomedical Research and Research Training	000	2	8/26/2024	SUPPLEMENT FOR EXPANSION	$87,515
														Subtotal = $448,125

Issue Date FY: 2023 ( Subtotal = $407,221 )
2023	2023	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	750 E ADAMS ST	SYRACUSE	NY	13210	ONONDAGA	USA	Biomedical Research and Research Training	000	2	8/7/2023	NON-COMPETING CONTINUATION	$407,221
														Subtotal = $407,221

Issue Date FY: 2022 ( Subtotal = $435,921 )
2022	2022	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	750 E ADAMS ST	SYRACUSE	NY	13210	ONONDAGA	USA	Biomedical Research and Research Training	000	1	9/19/2022	NEW	$435,921
														Subtotal = $435,921

Grand Total All Awards = $1,628,043

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Combining protein and DNA engineering to create bioswitches

Award Number: R01GM148448

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: 09/20/2022

PERIOD OF PERFORMANCE END DATE: 08/31/2026

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