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Development of approaches to apply CRISPR/Cas9-mediated gene conversion to model complex genetic traits in mice

Award Number: R01GM148640
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: 02/01/2023
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Development of approaches to apply CRISPR/Cas9-mediated gene conversion to model complex genetic traits in mice - PROJECT SUMMARY Decades of research using laboratory mice and rats have revealed mechanisms of human development and disease. It is highly likely that rodents have provided critical supporting data for clinical trials of every pharmaceutical or therapeutic approach currently used to improve human health. There are, however, limitations to the utility of mice and rats to understand and model complex genetic problems (e.g. Alzheimer's, heart disease, and diabetes) due to the rare probability of inheriting desired alleles at four or more loci and the small litter size compared to offspring of other traditional model species. The cost, time, and number of animals needed to model complex genetic traits would be reduced by an approach to increase the probability one of the two alleles at multiple loci will be transmitted to the next generation. CRISPR/Cas9-mediated gene conversion, which is feasible in mice, can perhaps accomplish exactly this goal by copying genetic information from a donor to a recipient allele in the germline. Briefly, this occurs by germline-restricted expression of genetically encoded Cas9 and a guide RNA (gRNA) that targets only the recipient and not the donor allele. If the double strand break in the recipient allele is repaired by interchromosomal homology directed repair, the recipient allele is replaced by the donor allele. CRISPR/Cas9- mediated gene conversion therefore changes the genotype of the cell from heterozygous to homozygous and ensures any resulting sperm or egg will transmit only the donor allele. The proposed objectives will build on proof-of-feasibility to improve the efficiency of CRISPR/Cas9 mediated gene conversion in the female and male mouse germline and to test the efficiency of gene conversion at two loci in the same cell. Previous work suggests a high level of Cas9 expression timed to initiate during early meiosis I is necessary for efficient gene conversion in both sexes. Aim1 of this proposal seeks to apply this knowledge to develop and test three BAC transgenic drivers of Cas9 expression using regulatory sequences of the meiotic genes Tex12, Prdm9, and Rad51ap2. To date, CRISPR/Cas9-mediated gene conversion has been assessed at one locus – Tyrosinase. Aim 2 seeks to quantify the efficiency of gene conversion at two additional loci individually and of two loci together in the same cell. Mathematical models predict the efficiency of multi-locus gene conversion, but empirical evidence is required to determine whether the actual efficiency follows a `multiplicative' or `coordinated' probability. The outcomes of this research are critical to maximize the utility and future biological impact of CRISPR/Cas9-mediated gene conversion approaches to model and solve a variety of genetically complex challenges to human health.


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 = $469,260 )
2026	2026	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	4	1/26/2026	NON-COMPETING CONTINUATION	$469,260
														Subtotal = $469,260

Issue Date FY: 2025 ( Subtotal = $521,400 )
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	3	4/30/2025	NON-COMPETING CONTINUATION	$521,400
														Subtotal = $521,400

Issue Date FY: 2024 ( Subtotal = $643,329 )
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	2	9/20/2024	NON-COMPETING CONTINUATION	$643,329
														Subtotal = $643,329

Issue Date FY: 2023 ( Subtotal = $521,400 )
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	1	1/30/2023	NEW	$521,400
														Subtotal = $521,400

Grand Total All Awards = $2,155,389

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Development of approaches to apply CRISPR/Cas9-mediated gene conversion to model complex genetic traits in mice

Award Number: R01GM148640

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: 02/01/2023

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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