R24OD031955
Project Grant
Overview
Grant Description
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 37°C. 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 a wide array of human regenerative and cancer cell types.
The overall objective is to:
I) 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.
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 span the mission of many NIH institutes.
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 37°C. 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 a wide array of human regenerative and cancer cell types.
The overall objective is to:
I) 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.
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 span the mission of many NIH institutes.
Awardee
Funding Goals
THE OFFICE OF RESEARCH INFRASTRUCTURE PROGRAMS (ORIP) IS A PROGRAM OFFICE IN THE DIVISION OF PROGRAM COORDINATION, PLANNING, AND STRATEGIC INITIATIVES (DPCPSI) DEDICATED TO SUPPORTING RESEARCH INFRASTRUCTURE AND RELATED RESEARCH RESOURCE PROGRAMS. ORIP CONSISTS OF THE DIVISION OF COMPARATIVE MEDICINE (DCM) AND THE DIVISION OF CONSTRUCTION AND INSTRUMENTS (DCI).
Grant Program (CFDA)
Awarding Agency
Place of Performance
Boston,
Massachusetts
021142621
United States
Geographic Scope
Single Zip Code
Related Opportunity
Analysis Notes
Amendment Since initial award the total obligations have increased 344% from $715,167 to $3,178,512.
The General Hospital Corporation was awarded
Optimized Zebrafish Xenograft Models for Preclinical Therapies
Project Grant R24OD031955
worth $3,178,512
from the National Institute of Allergy and Infectious Diseases in March 2022 with work to be completed primarily in Boston Massachusetts United States.
The grant
has a duration of 4 years and
was awarded through assistance program 93.351 Research Infrastructure Programs.
The Project Grant was awarded through grant opportunity Resource-Related Research Projects for Development of Animal Models and Related Materials (R24 Clinical Trials Not-Allowed).
Status
(Ongoing)
Last Modified 7/25/25
Period of Performance
3/1/22
Start Date
2/28/26
End Date
Funding Split
$3.2M
Federal Obligation
$0.0
Non-Federal Obligation
$3.2M
Total Obligated
Activity Timeline
Transaction History
Modifications to R24OD031955
Additional Detail
Award ID FAIN
R24OD031955
SAI Number
R24OD031955-945220310
Award ID URI
SAI UNAVAILABLE
Awardee Classifications
Nonprofit With 501(c)(3) IRS Status (Other Than An Institution Of Higher Education)
Awarding Office
75AGNA NIH AGGREGATE FINANCIAL ASSISTANCE DATA AWARDING OFFICE
Funding Office
75NA00 NIH OFFICE OF THE DIRECTOR
Awardee UEI
FLJ7DQKLL226
Awardee CAGE
0ULU5
Performance District
MA-08
Senators
Edward Markey
Elizabeth Warren
Elizabeth Warren
Budget Funding
| Federal Account | Budget Subfunction | Object Class | Total | Percentage |
|---|---|---|---|---|
| Office of the Director, National Institutes of Health, Health and Human Services (075-0846) | Health research and training | Grants, subsidies, and contributions (41.0) | $1,589,256 | 100% |
Modified: 7/25/25