(PQ 6) New Models of KSHV Oncogenesis and KS Immune Environment

(PQ 6) KSHV 肿瘤发生和 KS 免疫环境的新模型

基本信息

批准号：
10737765
负责人：
ETHEL CESARMAN
金额：
$ 23.9万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-15 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10737765
关键词：
3-Dimensional AIDS related cancer Acquired Immunodeficiency Syndrome Address Affect Africa South of the Sahara Animals Antibody Therapy Attention B-Lymphocytes Biopsy Blood Vessels CD4 Positive T Lymphocytes CD8B1 gene Cell Line Cells Chronic Clinical Complement 3d Cytometry Detection Development Disease Drug Targeting Elements Endothelial Cells Engineering Environment Etiology Evaluation Gene Expression Genes Genetically Engineered Mouse Goals Grant Growth HIV Human Human Herpesvirus 8 Hydrogels Image Immune Immunocompetent Immunodeficient Mouse Immunotherapy Implant In Vitro Individual Infection Inflammatory Inflammatory Infiltrate Kaposi Sarcoma Laboratories Lead Lesion Lymphoma Lymphoproliferative Disorders Lytic Macrophage Malignant Neoplasms Messenger RNA Methods Modeling Multicentric Angiofollicular Lymphoid Hyperplasia Mus Organoids Pathogenesis Pathology Patients Pattern Permeability Persons Pharmaceutical Preparations Phenotype Plasma Cells Process Proteins Research Rodent Role Schedule Signal Transduction Solid System T-Cell Depletion Testing Therapeutic Tissues Transcript Translating Translations Tumor Biology Viral Genes Viral Genome Viral Proteins Virus Virus Latency Xenograft procedure candidate identification checkpoint therapy chemotherapy common treatment histogenesis human disease immune cell infiltrate immunoregulation immunosuppressed in vivo in vivo Model mast cell mouse model neoplastic cell novel novel therapeutics organ transplant recipient pre-clinical primary effusion lymphoma resistance mechanism response targeted treatment therapeutic evaluation tumor tumor microenvironment tumor-immune system interactions tumorigenesis

项目摘要

PROJECT SUMMARY Kaposi's sarcoma (KS) is the most common cancer globally in people living with HIV, and among the most common cancers in Sub-Saharan Africa, and is caused by infection by the Kaposi sarcoma herpesvirus (KSHV, also called HHV-8). This virus also causes primary effusion lymphoma (PEL) and multicentric Castleman's disease (MCD). While PEL is rare, it is an aggressive malignancy with few therapeutic options. KSHV-associated diseases are difficult to model because this virus is species-specific, it does not transform cells in in culture, in vitro infection frequently leads to a mixture of latent and lytic viral gene expression, and related animal viruses do not cause the same pathologies. Furthermore, KS lesions are composed of a mixture of cells that include latently KSHV-infected spindle cells and a mixed inflammatory infiltrate that includes numerous CD8+ and CD4+ T cells, plasma cells, macrophages, and mast cells. While substantial attention has been given to the histogenesis of the spindle cells, the immune infiltrates in KS lesions have only been superficially and incompletely described. The overarching goal is this application is develop preclinical in vitro, ex vivo and in vivo models of KSHV-associated diseases, including KS, MCD and lymphoma. To model KS, we will apply observations from human lesions, and include the immune elements of this disease. This will be accomplished through the following specific aims: 1) conditional expression of major latency transcript genes in immunocompetent mice; 2) examine the tumor immune environment in KS lesions in patients and test the role of major immune subsets in mice; and 3) engineer synthetic, in vitro and ex vivo Kaposi sarcoma-like tissue niches for controlled growth of healthy and diseased primary endothelial cells. We will examine the effects of first line therapeutic approaches, targeted therapy and immunotherapy in these models to validate them for preclinical use.

项目摘要 Kaposi的肉瘤（KS）是全球最常见的癌症，在艾滋病毒中，是撒哈拉以南非洲最常见的癌症之一，是由Kaposi sarcoma疱疹病毒（KSHV，也称为HHV-8）的感染引起的。该病毒还会引起原发性积液淋巴瘤（PEL）和多中心Castleman病（MCD）。尽管PEL很少见，但它是一种侵略性的恶性肿瘤，几乎没有治疗选择。 KSHV相关的疾病很难建模，因为该病毒是物种特异性的，它不会在培养中转化细胞，体外感染经常导致潜在和裂解病毒基因表达的混合物，而相关的动物病毒不会引起相同的病理。此外，KS病变由细胞的混合物组成，包括潜在的KSHV感染的纺锤体细胞和混合炎性浸润，其中包括许多CD8+和CD4+ T细胞，血浆细胞，巨噬细胞和肥大细胞。尽管对纺锤体细胞的组织发生有很大的关注，但KS病变中的免疫浸润仅是表面上和未完全描述的。总体目标是该应用是在体外发展的临床前，体内和KSHV相关疾病的体内模型，包括KS，MCD和淋巴瘤。为了建模KS，我们将采用人类病变中的观察结果，并包括该疾病的免疫元素。这将通过以下特定目的来完成：1）免疫能力小鼠中主要潜伏期转录基因的条件表达； 2）检查患者KS病变中的肿瘤免疫环境，并测试小鼠主要免疫亚群的作用； 3）工程师合成，体外和离体Kaposi肉瘤样组织壁ni，用于控制健康和患病的原发性内皮细胞的生长。我们将研究这些模型中第一线治疗方法，靶向治疗和免疫疗法的影响，以验证它们以临床前的使用。