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Mechanisms of CRISPR-mediated immunity and applications beyond editing

Award Number: K99GM147842
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 08/01/2022
PERIOD OF PERFORMANCE END DATE: 01/19/2024

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Mechanisms of CRISPR-mediated immunity and applications beyond editing - PROJECT SUMMARY/ABSTRACT 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. My preliminary bioinformatics analysis of CRISPR leaders (upstream DNA) has revealed subtype- and microbe-specific motifs. These conserved motifs are found in a tight distribution of positions relative to the leader-CRISPR junction, and positional variants are shifted by a helical turn of DNA that would preserve the presentation of these motifs on the same face of DNA. In Aim 1, I will determine the structures of biochemically trapped CRISPR integration complexes to determine the roles of leader motifs and host proteins in regulating integration. In Aim 2, I will determine a biochemical and structural understanding of immune proteins that I predict to be activated by CRISPR-generated nucleotide messengers. This tailored application will support my transition to an independent academic position through: i) Structural biology training, ii) Mentoring, communication, and grant writing training, iii) Identification of novel CRISPR adaptation regulatory motifs and, iv) Identification of novel immune effectors. I will take formal cryo-EM coursework provided at Montana State 'University's (MSUs) cryo-EM facility by co-advisor Dr. Lawrence and co-mentor Dr. Lander, supplemented by coursework at NIH's National Center for Cryo-EM Access and Training. I will further develop my mentoring, communication, and grant writing skills through coursework provided by 'MSU's Center for Faculty excellence and by ASBMB's UE5 component. I have recruited a mentoring and advisory committee of six scientists with complementary expertise in CRISPR biology, the development of CRISPR-based applications, cryo-EM methodology, virology, and infectious diseases - relevant to guiding me as I pursue my research and career goals. The proposed project provides me with training in cryo-EM structural biology. It provides me with foundational bioinformatic and biochemical data that will serve as a springboard for my independent lab's interdisciplinary research on CRISPR biology and its applications. There, I aim to serve as a mentor for the next generation of underrepresented minority scientists.


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 = $0 )
2025	2023	MONTANA STATE UNIVERSITY	216 MONTANA HALL	BOZEMAN	MT	59717	GALLATIN	USA	Biomedical Research and Research Training	001	2	10/29/2024	NON-COMPETING CONTINUATION	$0
2025	2022	MONTANA STATE UNIVERSITY	216 MONTANA HALL	BOZEMAN	MT	59717	GALLATIN	USA	Biomedical Research and Research Training	000	1	10/29/2024	NEW	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = -$73,257 )
2024	2023	MONTANA STATE UNIVERSITY	216 MONTANA HALL	BOZEMAN	MT	59717	GALLATIN	USA	Biomedical Research and Research Training	000	2	12/21/2023	NON-COMPETING CONTINUATION	-$54,375
2024	2023	MONTANA STATE UNIVERSITY	216 MONTANA HALL	BOZEMAN	MT	59717	GALLATIN	USA	Biomedical Research and Research Training	001	2	9/10/2024	NON-COMPETING CONTINUATION	-$18,882
														Subtotal = -$73,257

Issue Date FY: 2023 ( Subtotal = $125,000 )
2023	2023	MONTANA STATE UNIVERSITY	216 MONTANA HALL	BOZEMAN	MT	59717	GALLATIN	USA	Biomedical Research and Research Training	000	2	7/13/2023	NON-COMPETING CONTINUATION	$125,000
														Subtotal = $125,000

Issue Date FY: 2022 ( Subtotal = $100,000 )
2022	2022	MONTANA STATE UNIVERSITY	216 MONTANA HALL	BOZEMAN	MT	59717	GALLATIN	USA	Biomedical Research and Research Training	000	1	7/19/2022	NEW	$100,000
														Subtotal = $100,000

Grand Total All Awards = $151,743

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Mechanisms of CRISPR-mediated immunity and applications beyond editing

Award Number: K99GM147842

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 08/01/2022

PERIOD OF PERFORMANCE END DATE: 01/19/2024

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