Identifying therapeutic pathways targeting medulloblastoma-immune cell interactions

确定针对髓母细胞瘤-免疫细胞相互作用的治疗途径

基本信息

批准号：
10219682
负责人：
Ernest Fraenkel
金额：
$ 59.4万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
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：
2021-05-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10219682
关键词：
Address Binding Blood Blood - brain barrier anatomy Blood Circulation Brain Brain Neoplasms CD47 gene Cell Communication Cell Surface Proteins Cell surface Cells Childhood Brain Neoplasm Childhood Malignant Brain Tumor Clinical Clinical Data Computer Analysis Computer Models Data Dendritic Cells Disease model Environment Genes Human Immune Immune system Immunofluorescence Immunologic Immunologic Markers Immunologic Surveillance Immunomodulators Immunooncology Immunosuppression Immunotherapy Intervention Ligands Link Major Histocompatibility Complex Malignant Neoplasms Maps Methods Microglia Modeling Molecular Mus Natural Killer Cells Outcome Pathway interactions Patients Periodicity Peripheral Property Proteins Proteomics Regulation Regulatory Pathway Research SHH gene Sampling Sampling Studies Shapes Signal Transduction Site Solid Neoplasm Stream Surface Surface Antigens Systems Biology T-Lymphocyte TNF gene TP53 gene Testing Therapeutic Therapeutic Intervention Translating Tumor Subtype Tumor-associated macrophages Tumor-infiltrating immune cells Update Variant Work base causal model cell type clinically relevant cytokine experimental study genetic regulatory protein imaging modality immunoreaction immunoregulation improved innovation insight macrophage medulloblastoma mouse model multi-scale modeling mutant neoplastic cell novel outcome prediction phosphoproteomics protein expression single-cell RNA sequencing targeted treatment therapeutic candidate therapeutic development therapeutic evaluation therapeutic target transcriptomics tumor tumor growth tumor-immune system interactions

项目摘要

SUMMARY We propose developing a systems-biology approach to understand interactions between tumor and immune cells and their clinical implications. Our work will focus on medulloblastoma, a malignant pediatric brain tumor in which our team has extensive expertise. We and others have shown that medulloblastoma tumors are sites of immune activity despite the blood-brain barrier. However, the clinical consequences of these immune cells are unclear and there is little information that might guide development of therapeutics that modulate these immune cells. Our innovative strategy combines single-cell methods, including single-cell proteomics, with a sophisticated computational analysis. In Aim 1, we map the landscape of tumor-immune interactions using sequencing and imaging methods on human samples. Aim 2 builds a causal model of the molecular interactions that govern interactions among cell types in medulloblastoma, determines the clinical correlates of these cells, and identifies potential therapeutic targets. Aim 3 maps the tumor-immune environment in well-validated mouse models of the disease, and builds computational models for mice parallel to those for humans. Hypotheses from Aim 2 that are likely to translate well to the mouse models are then tested for their effects on tumor growth and survival. The mouse results are used to update the computational models and refine the therapeutic strategies. We expect that successful completion of this project will have a substantial impact on medulloblastoma therapeutics. Further, the methods we develop will catalyze research of interactions between immune cells and many other tumor types beyond medulloblastoma.

概括我们建议开发一种系统生物学方法来了解肿瘤与免疫之间的相互作用细胞及其临床意义。我们的工作将集中于髓母细胞瘤，这是一种恶性小儿脑肿瘤我们的团队拥有广泛的专业知识。我们和其他人表明髓母细胞瘤是部位尽管存在血脑屏障，但免疫活性。但是，这些免疫细胞的临床后果尚不清楚，很少有信息可以指导调节这些治疗剂的开发免疫细胞。我们的创新策略结合了包括单细胞蛋白质组学在内的单细胞方法和精致计算分析。在AIM 1中，我们使用测序和人类样品的成像方法。 AIM 2建立了控制分子相互作用的因果模型髓母细胞瘤中细胞类型之间的相互作用，确定这些细胞的临床相关性，并确定确定潜在的治疗靶标。 AIM 3映射验证的鼠标中的肿瘤免疫环境该疾病的模型，并为小鼠与人类平行的小鼠建立计算模型。假设然后从AIM 2转换为鼠标模型，然后测试其对肿瘤的影响生长和生存。鼠标结果用于更新计算模型并完善治疗策略。我们预计该项目的成功完成将对髓母细胞瘤疗法。此外，我们开发的方法将催化对相互作用的研究免疫细胞和许多其他肿瘤类型以外的髓母细胞瘤。