Mechanisms of neuroinflammation in brain metastasis progression

神经炎症在脑转移进展中的机制

• 批准号: 10201524
• 负责人: Siyuan Zhang
• 金额: $ 37.38万
• 依托单位: UNIVERSITY OF NOTRE DAME
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10201524
• 关键词: Adjuvant Therapy; Algorithmic Analysis; Antineoplastic Agents; Architecture; Basic Science; Behavior; Blood - brain barrier anatomy; Bone Marrow; Brain; Brain Neoplasms; Cancer Survivor; Cells; Clinic; Clinical; Clinical Treatment; Coupled; Data; Development; Diagnosis; Fright; Future; Genetic; Genetic Variation; Genomic approach; Genotype; Global Change; Goals; Heterogeneity; ITGAM gene; Image Analysis; Immune; Immune system; In Situ; Incidence; Inflammatory; Malignant Neoplasms; Malignant neoplasm of brain; Measures; Mediating; Metastatic malignant neoplasm to brain; Microglia; Modeling; Molecular; Myelogenous; Myeloid Cells; Neoplasm Metastasis; Neurodegenerative Disorders; Organ; Patients; Pattern; Phenotype; Plant Roots; Primary Neoplasm; Relapse; Research; Resolution; Role; Sampling; Screening for cancer; Site; Statistical Models; Therapeutic; Tissue Sample; Tissue imaging; Tissues; Transgenic Mice; Treatment Protocols; Validation; base; brain tissue; cell type; clinical practice; design; imaging approach; imaging modality; improved; innovation; insight; interdisciplinary approach; macrophage; malignant breast neoplasm; metastasis prevention; mortality; mouse model; multidisciplinary; neoplastic cell; neuroinflammation; new therapeutic target; novel; pre-clinical; pre-clinical research; preclinical efficacy; receptor; single-cell RNA sequencing; spatiotemporal; success; targeted treatment; trait; transcriptome; tumor progression

Project Summary Title: Mechanisms of neuroinflammation in brain metastasis progression Despite significant progress in early cancer screening and treatment regimens for primary tumors, the overall mortality of patients with metastatic relapse has not improved in the past two decades. Many sites of metastatic relapse are commonly diagnosed in the clinic, but brain metastasis is the most devastating with a median survival of fewer than six months. Thriving in a "sanctuary" protected by the blood-brain barrier (BBB), brain metastases are shielded from most anti-cancer drugs. As a result, the incidence of brain metastasis is increasing, despite increasing control of primary tumors. Thus, to reduce cancer mortality, rationally designed therapeutics, based on a mechanistic understanding of metastasis in the context of the unique brain microenvironment, are urgently needed for brain metastasis patients. The immune system has indisputable and ubiquitous roles in regulating both primary tumors and metastases. Traditionally viewed as immunoprivileged organ, the role of neuroinflammation in brain tumor progression is largely underexplored. In this proposed study, we will use transgenic mouse models and state-of-the-art genomics and imaging approach to trace and analyze the role of highly heterogeneous cell types involved in neuroinflammation and their roles in regulating brain metastatic outgrowth. This collaborative effort from a multidisciplinary team, including a cancer biologist, an expert in neuroinflammation, a computational biologist and a bioinformatician and will allow us to: 1) dissect distinct contribution subpopulation of myeloid cells in regulating brain metastasis at phenotypical level (Aim 1); 2) visualize and quantitatively measure the behavior of brain microenvironmental niche and transcriptome heterogeneity of inflammatory myeloid cell that that nurtures metastasis in brain (Aim 2). 3) Targeting pro-inflammatory myeloid cells as means of brain metastasis prevention. Shifting the current clinical treatment model relies on new in-depth mechanistic insights obtained through basic and pre-clinical innovative research. Utilizing cutting-edge sequencing and imaging modality coupled with classic transgenetic models and clinical tissue samples, we now have the unprecedented capacity to systematically dissect the traits of metastatic behavior and discover potential novel therapeutic targets for paradigm-shifting novel adjuvant therapy for brain metastasis patients.

项目摘要 标题：脑转移瘤进展过程中神经炎症的机制 尽管在早期癌症筛查和原发肿瘤的治疗方案方面取得了重大进展， 在过去的二十年中，转移性复发患者的总体死亡率没有改善。许多遗址 转移性复发通常在临床上被诊断出来，但脑转移是最具破坏性的 中位生存期不到6个月。在一个由血脑屏障(BBB)保护的“避难所”中茁壮成长， 大多数抗癌药物都能保护脑转移。因此，脑转移的发生率是 尽管增加了对原发肿瘤的控制，但这种情况仍在增加。因此，为降低癌症死亡率，合理设计 治疗学，基于对独特大脑背景下转移的机械性理解 微环境，是脑转移患者迫切需要的。免疫系统有无可争辩的 在调节原发肿瘤和转移方面的作用无处不在。传统上被视为 在免疫器官中，神经炎症在脑肿瘤进展中的作用在很大程度上还没有得到充分的研究。在……里面 在这项拟议的研究中，我们将使用转基因小鼠模型和最先进的基因组学和成像技术 追踪和分析高度异质性细胞类型在神经炎症和神经保护中的作用 它们在调节大脑转移性生长中的作用。这是一个多学科团队的协作努力， 包括一名癌症生物学家、一名神经炎症专家、一名计算生物学家和一名生物信息学家 这将使我们能够：1)剖析髓系细胞在调节脑转移中的不同贡献亚群 在表型水平(目标1)；2)可视化和定量测量大脑微环境的行为 促进脑转移的炎性髓系细胞的生态位和转录组的异质性(目的 2)。3)靶向炎性髓系细胞作为预防脑转移的手段。转移电流 临床治疗模式依赖于通过基础和临床前获得的新的深入机制见解 创新研究。利用尖端测序和成像手段结合经典转基因 模型和临床组织样本，我们现在拥有前所未有的能力来系统地解剖 转移行为的特点和发现范式转换小说潜在的治疗新靶点 脑转移瘤患者的辅助治疗。