Thursday, July 31, 2025 7/31/2025

Developing preclinical xenograft models in zebrafish.

Award Number: R24OD031955
ORGANIZATION: OFFICE OF THE DIRECTOR, NIH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2022
PERIOD OF PERFORMANCE END DATE: 02/28/2026

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Developing preclinical xenograft models in zebrafish. - PROJECT SUMMARY Xenograft cell transplantation has transformed our understanding of human disease and has been used extensively to assess regeneration, stem cell self-renewal, and cancer. Yet, mouse xenograft studies are expensive and not easily amenable to imaging engraftment at single cell resolution. By contrast, zebrafish are inexpensive, can be reared in large numbers, and are capable of real-time imaging of fluorescent-labeled cells at single cell resolution. Our group has recently pioneered the use of adult immune-deficient zebrafish for xenograft transplantation of human cancers and blood cells when reared at 37OC. Despite these successes, more needs to be done to develop the next generation of immune compromised zebrafish for long-term xenograft cell transplantation studies. The long-term goal of our work is to develop a universal zebrafish transplantation model to engraft of a wide array of human regenerative and cancer cell types. The overall objective is i) to develop new immune deficient zebrafish models for optimized xenograft engraftment of human cancer, embryonic and induced-pluripotent stem cells (ES and iPSCs), and blood cells and ii) provide much needed tools, methods, and cell biological readouts to directly assess pharmacodynamic responses to radiation, drugs, and cell biological immunotherapies in vivo. The rationale for our research is that zebrafish blood development is highly conserved and that developing zebrafish transplantation models will provide new tools to rapidly assess preclinical therapies in vivo and at single cell resolution. Aim 1 will develop compound mutant and transgenic zebrafish for optimized xenograft cell transplantation. We will develop new models that lack T, B, NK, and macrophage cell function and that transgenically express human cytokines to support the growth of human blood. We will also generate knock-in “genotype-less rag2∆/∆, il2rga−/− zebrafish” to increase throughput in identifying double homozygous mutant animals. Aim 2 will test these models for enhanced engraftment of human cancers, ES, iPSCs, and blood cells. This work is important, because it will provide novel models and experimental protocols to engraft a wide array of regenerative cell types. Aim 3 will dynamically visualize xenograft single cell responses to radiation, combination drug therapies, and immunotherapy in preclinical modeling studies. This work will provide much needed cell biological readouts to directly assess pharmacodynamic responses at single cell resolution across a wide array of therapies. These same imaging tools and approaches can be used in many xenograft models – including patient-derived xenografts (PDXs), ES/IPSCs, and blood. Our work is significant because it will develop the next generation of low-cost, high throughput cell transplantation models that allow direct visualization of engrafted cell behaviors in the context of preclinical therapies. This work will have a positive translational impact by developing preclinical animal models that efficiently engraft a wide array of human tissues. Such broad reaching applications for immune compromised zebrafish spans the mission of many NIH institutes.


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 = $794,628 )
2025	2025	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Research Infrastructure Programs	000	4	2/25/2025	NON-COMPETING CONTINUATION	$635,702
2025	2025	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Research Infrastructure Programs	001	4	7/21/2025	NON-COMPETING CONTINUATION	$158,926
														Subtotal = $794,628

Issue Date FY: 2024 ( Subtotal = $794,628 )
2024	2024	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Research Infrastructure Programs	000	3	2/15/2024	NON-COMPETING CONTINUATION	$635,702
2024	2024	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Research Infrastructure Programs	001	3	5/23/2024	NON-COMPETING CONTINUATION	$158,926
														Subtotal = $794,628

Issue Date FY: 2023 ( Subtotal = $794,628 )
2023	2023	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Research Infrastructure Programs	000	2	2/9/2023	NON-COMPETING CONTINUATION	$715,166
2023	2023	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Research Infrastructure Programs	001	2	2/23/2023	NON-COMPETING CONTINUATION	$79,462
														Subtotal = $794,628

Issue Date FY: 2022 ( Subtotal = $794,628 )
2022	2022	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Research Infrastructure Programs	000	1	2/23/2022	NEW	$715,167
2022	2022	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Research Infrastructure Programs	002	1	8/3/2022	NEW	$0
2022	2022	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Research Infrastructure Programs	001	1	5/5/2022	NEW	$79,461
														Subtotal = $794,628

Grand Total All Awards = $3,178,512

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Developing preclinical xenograft models in zebrafish.

Award Number: R24OD031955

ORGANIZATION: OFFICE OF THE DIRECTOR, NIH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 03/01/2022

PERIOD OF PERFORMANCE END DATE: 02/28/2026

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