Regulatory T cell modulation of reactive astrogliosis in brain metastasis

调节性 T 细胞调节脑转移中反应性星形胶质细胞增生

• 批准号: 10413558
• 负责人: Paula Daniela Bos
• 金额: $ 40.46万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10413558
• 关键词: Ablation; Amphiregulin; Applications Grants; Astrocytes; Astrocytoma; Bone Marrow; Bone Marrow Neoplasms; Brain; Brain Neoplasms; CCL2 gene; Calcium; Cancer Patient; Cell Line; Cell physiology; Cells; Development; Disease; Epidermal Growth Factor Receptor; Event; FOXP3 gene; Flow Cytometry; Fright; Genetic Models; Gliosis; Goals; Growth; Heterogeneity; Image; Immune response; Immunofluorescence Immunologic; Immunohistochemistry; Interferons; Lead; Lesion; Light; Malignant Neoplasms; Mediating; Metastatic malignant neoplasm to brain; Modeling; Neoplasm Metastasis; Neuraxis; Neurologic Symptoms; Neurons; Outcome; Pathology; Pathway interactions; Patients; Plasminogen Activator; Play; Population; Primary Neoplasm; Process; Production; Prognosis; Regulatory T-Lymphocyte; Research Proposals; Resistance; Role; STAT3 gene; Signal Transduction; Slice; Systemic Therapy; Therapeutic; Time; Tissues; Tumor Burden; astrogliosis; base; brain cell; brain tissue; cancer complication; chemotherapy; combat; effector T cell; immune checkpoint blockade; in vivo; metastatic process; mind control; neoplastic cell; novel; novel strategies; peripheral tolerance; receptor; recruit; response; stroke model; tissue repair; tumor

Project Summary The main goal of this grant proposal is to investigate the interaction between regulatory T (Treg) cells and reactive astrogliosis in the context of brain metastatic disease, and their impact on the brain metastatic process. Brain metastasis represents the final stage of cancer, for which very limited treatment is available. Inevitably, patients with brain metastasis succumb to disease in a very short time. There is a strong resistance to the initial development of brain metastasis, and the activation of astrocytes represents one of the earliest events observed during the establishment of brain lesions. Their dual role first opposing and then favoring brain metastatic progression has only started to be investigated. Treg cells colonize and expand in the inflamed brain tissue, and have been shown to inhibit reactive gliosis in a model of stroke. We have demonstrated that Treg cell ablation in early and late brain metastasis results in significant reduction of the brain tumor burden, and leads to extensive expansion of reactive astrogliosis. In this research proposal, we use a combination of in vivo genetic modeling, ex vivo brain organotypic slice cultures, immunohistochemistry, flow cytometry, and single cell RNASequencing to investigate the hypothesis that Treg cells promote the establishment and progression of brain metastasis by modulating the highly heterogenous and plastic reactive astrocyte population. Results from the proposed studies will illuminate the mechanisms of brain metastatic disease, and will provide novel opportunities based on a largely unexplored therapeutic niche.

项目摘要 这项拨款提案的主要目标是研究调节性T(Treg)细胞和 脑转移疾病背景下的反应性星形胶质细胞增生症及其对脑转移过程的影响。 脑转移是癌症的最后阶段，可用于治疗的药物非常有限。不可避免地， 脑转移患者在很短的时间内就会死于疾病。一开始有很强的阻力 脑转移的发展，星形胶质细胞的激活是观察到的最早的事件之一 在建立脑部损伤的过程中。它们的双重作用先是反对，然后是有利于脑转移 这方面的进展才刚刚开始调查。Treg细胞在发炎的脑组织中定植和扩张， 已被证明可以抑制中风模型中的反应性胶质细胞增生。我们已经证明了Treg细胞消融 在早期和晚期脑转移导致脑肿瘤负担显著减轻，并导致广泛的 反应性星形胶质细胞增多。在这项研究方案中，我们结合使用体内遗传建模， 体外脑器官型切片培养、免疫组织化学、流式细胞术和单细胞RNAs测序 探讨Treg细胞通过以下途径促进脑转移瘤的建立和发展的假说 调节高度异质性和可塑性反应的星形胶质细胞群体。拟议研究的结果 将阐明脑转移疾病的机制，并将在很大程度上提供新的机会 尚未开发的治疗利基市场。