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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：
10400097
负责人：
Ernest Fraenkel
金额：
$ 65.85万
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/10400097
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.

总结我们建议开发一种系统生物学方法来了解肿瘤和免疫之间的相互作用，细胞及其临床意义。我们的工作将集中在髓母细胞瘤，一种恶性小儿脑肿瘤我们的团队在这方面拥有广泛的专业知识。我们和其他人已经证明髓母细胞瘤是免疫系统的活动，尽管血脑屏障。然而，这些免疫细胞的临床后果目前还不清楚，几乎没有信息可以指导调节这些的治疗方法的开发。免疫细胞我们的创新策略结合了单细胞方法，包括单细胞蛋白质组学，计算分析在目标1中，我们使用测序和免疫学方法绘制了肿瘤-免疫相互作用的图景。人体样本的成像方法。目标2建立了一个因果关系模型的分子相互作用，髓母细胞瘤中细胞类型之间的相互作用，决定了这些细胞的临床相关性，确定潜在的治疗靶点。目的3绘制经过良好验证的小鼠中的肿瘤免疫环境该模型的疾病，并建立计算模型的小鼠平行于那些为人类。假设然后测试它们对肿瘤的作用，成长和生存。鼠标结果用于更新计算模型并细化治疗策略我们预计，该项目的成功完成将对以下方面产生重大影响：髓母细胞瘤治疗学。此外，我们开发的方法将促进研究免疫细胞和髓母细胞瘤以外的许多其他肿瘤类型。