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Mechanisms of CRISPR-mediated immunity and applications beyond editing

Award Number: R00GM147842
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: 08/01/2022
PERIOD OF PERFORMANCE END DATE: 01/19/2027

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Mechanisms of CRISPR-mediated immunity and applications beyond editing - The discovery of CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) systems led to creative new applications that are transforming science and medicine. However, the rapid discovery of new CRISPR systems outpaces our understanding of their biological roles in anti-phage defense and their development for novel applications. To acquire immunity to new phages, CRISPR-associated proteins (Cas1 and Cas2) integrate fragments of phage DNA ( spacers ) at the leader-end of the CRISPR locus, near the transcription start site. But how Cas1-2 recognizes the leader-end of the CRISPR remains poorly understood. Next, the CRISPR locus is transcribed and processed into guide RNAs that are loaded into surveillance complexes (i.e., Csm complex). Upon sensing viral RNA, the Csm complex makes cyclic oligonucleotide messengers that regulate CRISPR adaptation and nucleases critical for phage defense. But the biological roles of many of these immune effectors remain understudied. The 1961 discovery of regulatory DNA motifs kindled an interest in the grammatical rules of DNA motifs that control the storage and retrieval of genetic information. In Aim 1, I will use a bioinformatic approach to discover DNA motifs in CRISPR leaders with highly conserved sequences and positions, that I hypothesize regulate key steps in CRISPR biology such as integration, transcription, or RNA processing. I will determine the role of novel DNA motifs and host factors in CRISPR integration using in vitro biochemical assays and cryo-EM structural biology. Nucleotide messengers regulate critical cellular processes across the tree of life, including anti-viral immune responses, cell morphology, and motility. To address a growing need for rapid and sensitive diagnostics, I co-invented an innovative RNA-guided Csm system for sensitive and sequence-specific detection of SARS-CoV-2 RNA, that repurposes a nuclease immune effector. However, nucleases represent a fraction of the diversity of enzymatic activities predicted to be activated by nucleotide messengers. In Aim 2, I will determine a biochemical and structural understanding of novel immune proteins that I predict to be activated by CRISPR-generated nucleotide messengers.The long-term objectives of this proposal are to address knowledge gaps in our understanding of how bacterial CRISPR adaptive immune systems function and are regulated, and to repurpose basic mechanistic insights for the development of biotech and medical applications.


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: 2026 ( Subtotal = $224,100 )
2026	2026	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	000	5	1/22/2026	NON-COMPETING CONTINUATION	$224,100
														Subtotal = $224,100

Issue Date FY: 2025 ( Subtotal = $249,000 )
2025	2025	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	000	4	1/6/2025	NON-COMPETING CONTINUATION	$224,100
2025	2025	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	001	4	8/21/2025	NON-COMPETING CONTINUATION	$24,900
														Subtotal = $249,000

Issue Date FY: 2024 ( Subtotal = $267,882 )
2024	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	000	3	12/22/2023	EXTENSION WITH OR WITHOUT FUNDS	$249,000
2024	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	001	3	9/10/2024	EXTENSION WITH OR WITHOUT FUNDS	$18,882
														Subtotal = $267,882

Grand Total All Awards = $740,982

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Mechanisms of CRISPR-mediated immunity and applications beyond editing

Award Number: R00GM147842

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: 08/01/2022

PERIOD OF PERFORMANCE END DATE: 01/19/2027

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