(PQ6) Mesenchymal stem cell based and immunocompetent mouse models of HIV/AIDS KSHV-driven sarcomagenesis

(PQ6) 基于间充质干细胞和免疫活性的 HIV/AIDS 小鼠模型 KSHV 驱动的肉瘤发生

基本信息

批准号：
10228426
负责人：
Enrique A Mesri
金额：
$ 57.83万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-08 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10228426
关键词：
AIDS related cancer AIDS/HIV problem Acquired Immunodeficiency Syndrome Address Affect Animal Model Antibodies Antibody Therapy Automobile Driving Biology Bone Marrow Cancer Etiology Cell model Cells Collaborations Development Doxorubicin Engraftment Evaluation Fibroblast Growth Factor Genes Growth HIV HIV Infections HIV-1 Herpesviridae Herpesviridae Infections Human Human Herpesvirus 8 Human immunodeficiency virus test IGF2 gene Immune Immune checkpoint inhibitor Immunocompetent Immunologic Deficiency Syndromes Immunologic Tests Immunologics Immunosuppression Immunotherapeutic agent Immunotherapy In Vitro Inbred BALB C Mice Incidence Individual Infection Inflammatory Kaposi Sarcoma Local Therapy Mesenchymal Stem Cells Modeling Molecular Genetics Morbidity - disease rate Mus Mutation Nude Mice Oncogenes Oncogenic PD-1/PD-L1 PDGFRA gene Pathogenesis Patients Phenotype Phosphotransferases Populations at Risk Pre-Clinical Model Preclinical Testing Principal Investigator Proteins Role Study models System T-Lymphocyte Testing Therapeutic Translational Research Transplantation Tumorigenicity Viral Virus Virus Diseases antiretroviral therapy base chemotherapy co-infection common treatment cytokine design epigenome exhaustion global health immunoregulation immunosenescence immunosuppressed imprint in vivo in vivo Model innovation lymph nodes macrophage mortality mouse model mutant neoplastic cell novel novel therapeutic intervention novel therapeutics pre-clinical pre-clinical research programmed cell death ligand 1 programs stem cell model targeted treatment transcriptome tumor tumor growth tumorigenesis tumorigenic virology

项目摘要

Kaposi’s sarcoma is an HIV/ AIDS associated malignancy that in spite of the implementation of ART causes significant morbidity and mortality. Pathogenesis based design and testing of new therapeutic approaches are hampered by the paucity of models that reproduce KSHV oncogenesis in the HIV/AIDS setting. There are three major gaps to the experimental ability to model AIDS-KS in vitro and in vivo for translational and preclinical research. 1) A continuous in vitro KSHV-infection to tumorigenesis model that could help dissect microenvironment contributions, and dissect viral and host contributions to viral oncogenesis 2) An in vitro and in vivo model where HIV contributions to KSHV-sarcomagenesis can be identified and studied 3) An immunocompetent model of KSHV-tumorigenesis that could be used to test immune-based therapies. The Mesri and Roy Labs collaboratively developed a comprehensive set of cell and animal models of KSHV-driven Kaposi’s sarcoma that include. I) A mesenchymal-stem cell KSHV- infection to tumorigenesis system--a “de novo” KSHV-induced sarcomagenesis in vitro and in vivo model, which is tightly dependent on the infected-cell microenvironment for tumorigenicity II) A set of mouse models in which KSHV tumorigenesis occurs and can be studied in the context of immunodeficiency, HIV-infection contributions to tumorigenesis and KSHV tumorspecific immunosuppression III) A unique model in which KSHV-infected tumors can be transplanted and grown in HIV infected Balb/c mice. In Aim (1) we will use the MSCs models study the role of KSHV and HIV interactions in viral oncogenesis of HIV/AIDS-KS. In Aim (2) we will determine the mechanisms whereby HIV infection promotes KSHV tumorigenicity in nude and immunocompetent mice. In Aim (3), we will use our model of KSHV-tumorigenesis in HIV infected immunocompetent mice as AIDS-KS preclinical model. We will be able to test immunological therapies to KS such as immunomodulatory molecules, antibody-targeted therapies and checkpoint inhibitor immunotherapies. The propose studies provide unique mouse models to study the role of KSHV HIV co-infection in the pathogenesis of HIV/AIDS-associated Kaposi’s sarcoma and will serve to pre-clinically evaluate novel AIDS-KS therapeutic treatments.

卡波西的肉瘤是与艾滋病毒/艾滋病相关的恶性肿瘤，尽管实施了艺术会引起明显的发病率和死亡率。基于发病机理的新设计和测试繁殖KSHV的模型的匮乏阻碍了治疗方法艾滋病毒/艾滋病环境中的肿瘤发生。实验能力有三个主要差距体外和体内的模型艾滋病 - 用于翻译和临床前研究。 1）连续体外KSHV感染与肿瘤发生模型，可以帮助剖析微环境贡献，并剖析病毒和宿主对病毒肿瘤发生的贡献2）体外和可以鉴定对KSHV - 萨克素化作用的HIV贡献的体内模型，并研究3） KSHV - 肿瘤发生的免疫功能模型，可用于测试基于免疫的肿瘤。疗法。 Mesri和Roy Labs合作开发了一组全面的单元格，包括KSHV驱动的Kaposi肉瘤的动物模型。 i）间充质 - 茎细胞kshv- 对肿瘤发生系统的感染 - “从头” KSHV诱导的体外和体内的肌瘤作用模型，密切取决于感染细胞微环境的肿瘤性ii）a kshv肿瘤发生发生的一组小鼠模型，可以在免疫缺陷，HIV感染对肿瘤发生的贡献和KSHV特异性免疫抑制iii）一个独特的模型，其中可以移植KSHV感染的肿瘤并在艾滋病毒感染的BALB/C小鼠中生长。目的（1）我们将使用MSCS模型研究KSHV的作用 HIV/AIDS-K的病毒肿瘤发生中的HIV相互作用。在目标（2）我们将确定 HIV感染促进了裸体和免疫能力小鼠。在AIM（3）中，我们将在感染的HIV中使用我们的KSHV - 肿瘤发生模型免疫能力小鼠作为AIDS-KS临床前模型。我们将能够测试免疫学诸如免疫调节分子，抗体靶向疗法和诸如KS的疗法检查点抑制剂免疫疗法。提案研究为鼠标模型提供了独特的模型研究KSHV HIV共感染在HIV/AIDS相关Kaposi的发病机理中的作用肉瘤并将用于临时评估新颖的AIDS-KS治疗治疗方法。