(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.

卡波西肉瘤是一种与艾滋病毒/艾滋病相关的恶性肿瘤，尽管实施了 ART 导致显着的发病率和死亡率。基于发病机制的新设计和测试。缺乏再现 KSHV 的模型阻碍了治疗方法 HIV/艾滋病环境中的肿瘤发生存在三个主要的实验能力差距。用于转化和临床前研究的体外和体内模型 AIDS-KS 1) 连续研究。体外 KSHV 感染肿瘤发生模型有助于剖析微环境贡献，并剖析病毒和宿主对病毒肿瘤发生的贡献 2) 体外和体内可以识别和研究 HIV 对 KSHV 肉瘤发生的贡献的体内模型 3) KSHV 肿瘤发生的免疫活性模型可用于测试基于免疫的 Mesri 和 Roy 实验室合作开发了一套全面的细胞和疗法。 KSHV 驱动的卡波西肉瘤动物模型包括 I) 间充质干细胞 KSHV-。感染肿瘤发生系统——体外和体内“从头”KSHV诱导的肉瘤发生模型，其致瘤性紧密依赖于受感染细胞微环境 II) A 一组发生 KSHV 肿瘤发生并可在以下背景下进行研究的小鼠模型免疫缺陷、HIV 感染对肿瘤发生的贡献以及 KSHV 肿瘤特异性免疫抑制 III) 一种独特的模型，可以移植 KSHV 感染的肿瘤并在 HIV 感染的 Balb/c 小鼠中生长。在目标 (1) 中，我们将使用 MSC 模型研究 KSHV 的作用。和 HIV 在 HIV/AIDS-KS 病毒肿瘤发生中的相互作用。在 Aim (2) 中，我们将确定 HIV感染促进裸鼠和裸鼠KSHV致瘤性的机制在目标 (3) 中，我们将在 HIV 感染中使用我们的 KSHV 肿瘤发生模型。免疫活性小鼠作为AIDS-KS临床前模型我们将能够测试免疫学。 KS 疗法，如免疫调节分子、抗体靶向疗法和检查点抑制剂免疫疗法提供了独特的小鼠模型。研究 KSHV HIV 合并感染在 HIV/AIDS 相关卡波西病发病机制中的作用肉瘤，并将用于临床前评估新型 AIDS-KS 治疗方法。