Core B: Animal Model and Immunotyping Core

核心 B：动物模型和免疫分型核心

基本信息

批准号：
10704234
负责人：
THOMAS A. HAMILTON
金额：
$ 38.49万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
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：
2022-09-13 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10704234
关键词：
Address Affect Animal Model Autologous Bioinformatics CD8-Positive T-Lymphocytes Cancer Model Cell surface Cells Charge Consultations Crossbreeding Cytokine Network Pathway Cytokine Signaling Data Data Analyses Dendritic Cells Detection Dissection Dose Ensure Fibroblasts Flow Cytometry Fluorescence-Activated Cell Sorting Fostering Genetically Engineered Mouse Goals Growth Head and Neck Squamous Cell Carcinoma Human IL17 gene Immune Immune checkpoint inhibitor Immunocompetent Immunocompromised Host Immunotherapy Individual Inflammation Inflammatory Infrastructure Interferon-beta Interferons KRASG12D Kinetics Knock-in Mouse Libraries Lung Adenocarcinoma Malignant Neoplasms Malignant neoplasm of lung Measures Mission Modeling Molecular Mouse Strains Mus Myeloid Cells Outcome Pathway interactions Peripheral Blood Mononuclear Cell Procedures Protocols documentation Research Personnel Resistance Role STAT2 gene Sampling Services Shapes Signal Pathway Standardization Sting Injury Suspensions Testing Th1 Cells Therapeutic Tissues Transcend Transforming Growth Factor beta Tumor Biology Tumor Cell Line Tumor Immunity Tumor Promotion Tumor Tissue Work Xenograft Model cancer type cell type checkpoint therapy chemotherapy cytokine design experience experimental study fluorophore humanized mouse immune checkpoint blockade improved in vivo inflammatory milieu instrumentation member mouse model novel therapeutic intervention patient derived xenograft model pre-clinical pre-clinical assessment programs response single cell sequencing tissue preparation tool transcriptome sequencing transcriptomics treatment response triple-negative invasive breast carcinoma tumor tumor microenvironment tumor progression tumor xenograft

项目摘要

Project Summary Our preliminary data suggested a shared paradigm for the impact of the STING-IFN-β/TGFβ/IL-17 cytokine network on tumor progression and responses to therapy, which transcends the tissue origins of each cancer. Our goal, to unravel the crosstalk and define the paradigms, necessitates standardization of the protocols and procedures used by each constituent project, in order to unify our approaches in establishing preclinical tumor models and measuring tumor responses to therapy. Our ability to reach meaningful conclusions critically hinges on comparable execution of in vivo studies. Furthermore, a common readout shared by all three constituent projects is the inflammatory status in the TME. While immune-supportive inflammation (CD8, Th1, and dendritic cells) is associated with favorable responses to immune checkpoint inhibitor therapy, an immune-suppressive inflammatory environment (immature myeloid cells and fibroblasts) can antagonize anti-tumor immunity. Accurate detection, characterization and quantification of multiple cell types by flow cytometry and single-cell sequencing are crucial for assessing the state of intra-tumoral inflammation. A shared infrastructure that enables reliable analysis of the TME is essential for studying cytokine crosstalk. Taken together, the Animal Model and Immunotyping Core will be charged with two missions. First, the Core will provide technical and experimental infrastructure to enable uniform and standard in vivo analyses, including preclinical assessment of cancer therapeutics and characterization of the TME. Secondly, the Core will function as a hub for interaction among the constituent projects, including analytics assistance and scientific consultation on analyses of the TME.

项目摘要我们的初步数据提出了对Sting-IFN-β/TGFβ/IL-17细胞因子的影响的共同范例肿瘤进展的网络和对治疗的反应，它超越了每种癌症的组织起源。我们的目标是揭开串扰并定义范式，协议的必要标准化和每个构造项目使用的程序，以统一我们在建立临床前肿瘤方面的方法模型和测量肿瘤对治疗的反应。我们得出有意义的结论的能力严格取决于关于体内研究的可比执行。此外，这三个成分共享的常见读数项目是TME的炎症状态。而免疫支持炎症（CD8，TH1和树突状细胞）与免疫检查点抑制剂治疗的有利反应有关，这是一种免疫抑制炎症环境（未成熟的髓样细胞和成纤维细胞）可以拮抗抗肿瘤免疫学。通过流式细胞术和单细胞的精确检测，表征和数量多种细胞类型测序对于评估肿瘤内基础设施状态至关重要。一个共享的基础架构 TME的可靠分析对于研究细胞因子串扰至关重要。两者一起，动物模型和免疫型核心将被控两个任务。首先，核心将提供技术和实验性基础架构可以实现统一和标准的体内分析，包括对癌症的临床前评估 TME的治疗和表征。其次，核心将充当相互作用的枢纽组成项目，包括有关TME分析的分析援助和科学咨询。