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Developing preclinical xenograft models in zebrafish.

在斑马鱼中开发临床前异种移植模型。

基本信息

批准号：
10334672
负责人：
David Michael Langenau
金额：
$ 79.46万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-01 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10334672
关键词：
Ablation Address Adult Animal Model Animals Apoptosis B-Lymphocytes Biological Biological Immunotherapy Blood Blood Cells CD34 gene Cell Cycle Cell Death Cell Transplantation Cell division Cell physiology Cells Clinical Combination Drug Therapy Communities DNA Damage Development Embryo Engraftment Genotype Goals Growth Human Image Imaging Device Immune Immunotherapy Institutes Knock-in Label Laboratories Malignant Neoplasms Methods Mission Modeling Mus National Heart, Lung, and Blood Institute National Institute of Arthritis and Musculoskeletal and Skin Diseases National Institute of Child Health and Human Development National Institute of Diabetes and Digestive and Kidney Diseases National Institute of Neurological Disorders and Stroke Natural Killer Cells Natural regeneration Neoplasm Metastasis Optics Pharmaceutical Preparations Pharmacodynamics Positioning Attribute Pre-Clinical Model Protocols documentation Radiation Recording of previous events Recovery Research Resolution Rhabdomyosarcoma Study models T-Lymphocyte Testing Therapeutic Therapy Evaluation Transgenic Organisms Transplantation Umbilical Cord Blood United States National Institutes of Health Visualization Work Xenograft Model Xenograft procedure Zebrafish cancer cell cell behavior cell growth cell type cellular imaging chimeric antigen receptor T cells cost cytokine drug sensitivity fluorescence imaging human disease human imaging human tissue imaging approach imaging platform in vivo in vivo Model induced pluripotent stem cell inhibitor macrophage malignant muscle neoplasm mutant neoplastic cell next generation novel novel therapeutics patient derived xenograft model pre-clinical pre-clinical therapy radiation response real-time images regenerative biology regenerative cell regenerative tissue response self-renewal stem cell self renewal stem cells success temozolomide tool translational impact transplant model treatment response tumor tumor growth

项目摘要

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.

项目总结