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Determining the specificity and regulation of Type III CRISPR-Cas interference

Award Number: R35GM142966
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: 09/01/2021
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Determining the specificity and regulation of Type III CRISPR-Cas interference - Project Summary CRISPR (clustered regularly interspaced short palindromic repeats) and CRISPR-associated (Cas) proteins are a group of diverse crRNA guided nucleases providing prokaryotes adaptive immunity to foreign genetic elements. Cas10-Csm is an approximately 300 kDa multiprotein complex that upon detecting foreign RNA transcripts initiates a DNA and RNA degradation response. Distinct CRISPR-Cas types use the information in crRNA to detect either double-stranded DNA or single-stranded RNA. While much is known concerning the specificity mechanisms of dsDNA detection by Type I (Cascade) and Type II (Cas9) systems, little is known concerning the specificity mechanisms of ssRNA detection by Type III (Cas10) systems. This is significant because evidence exists that the mechanisms for enforcing specificity during dsDNA detection and ssRNA detection are fundamentally different: competition between rehybridization of the non-base paired DNA strand to re-form dsDNA or binding to a Cas protein is essential to the dsDNA detecting specificity mechanism. This mechanism is not possible during specific detection of ssRNA. The hypothesis will be tested that in the Cas10- Csm system mismatches in specific, sensitive locations within the crRNA-target RNA duplex disrupt interference. Cas10-Csm structural models suggest the Csm2 component of Cas10-Csm directly contacts bound target RNA. We will test the hypothesis that Csm2 plays an integral role in detecting cognate RNA binding to Cas10-Csm and relays this signal to Cas10 via structural changes. We will use cryo-EM to determine the `structural mechanism' for Cas10 activation. The research proposed will impact several emerging biotechnologies such as the deployment of Cas10 as a point-of-care RNA virus diagnostic.


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 = $351,646 )
2025	2025	UNIVERSITY OF ALABAMA	801 UNIVERSITY BLVD	TUSCALOOSA	AL	35401	TUSCALOOSA	USA	Biomedical Research and Research Training	000	5	6/5/2025	NON-COMPETING CONTINUATION	$351,646
														Subtotal = $351,646

Issue Date FY: 2024 ( Subtotal = $351,537 )
2024	2024	UNIVERSITY OF ALABAMA	801 UNIVERSITY BLVD	TUSCALOOSA	AL	35401	TUSCALOOSA	USA	Biomedical Research and Research Training	000	4	7/8/2024	NON-COMPETING CONTINUATION	$351,537
														Subtotal = $351,537

Issue Date FY: 2023 ( Subtotal = $353,278 )
2023	2023	UNIVERSITY OF ALABAMA	301 ROSE ADMIN BLDG	TUSCALOOSA	AL	35487	TUSCALOOSA	USA	Biomedical Research and Research Training	000	3	6/30/2023	NON-COMPETING CONTINUATION	$353,278
														Subtotal = $353,278

Issue Date FY: 2022 ( Subtotal = $355,717 )
2022	2022	UNIVERSITY OF ALABAMA	301 ROSE ADMIN BLDG	TUSCALOOSA	AL	35487	TUSCALOOSA	USA	Biomedical Research and Research Training	000	2	6/9/2022	NON-COMPETING CONTINUATION	$355,717
														Subtotal = $355,717

Issue Date FY: 2021 ( Subtotal = $368,258 )
2021	2021	UNIVERSITY OF ALABAMA	301 ROSE ADMIN BLDG	TUSCALOOSA	AL	35487	TUSCALOOSA	USA	Biomedical Research and Research Training	000	1	8/24/2021	NEW	$368,258
														Subtotal = $368,258

Grand Total All Awards = $1,780,436

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Determining the specificity and regulation of Type III CRISPR-Cas interference

Award Number: R35GM142966

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: 09/01/2021

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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