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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要该赠款提案的主要目的是研究调节t（Treg）细胞与在脑转移性疾病的背景下，反应性星形胶质细胞症及其对脑转移过程的影响。脑转移代表了癌症的最后阶段，为此提供非常有限的治疗方法。不可避免地脑转移的患者在很短的时间内屈服于疾病。最初有强烈的抵抗力脑转移的发展，星形胶质细胞的激活代表了观察到的最早事件之一在建立脑病变期间。他们的双重角色首先反对，然后偏爱大脑转移进步才开始研究。 Treg细胞在发炎的脑组织中定植和扩展，并且已显示在中风模型中抑制反应性神经胶质病。我们已经证明了Treg细胞消融在早期和晚期，脑转移会大大减轻脑肿瘤负担，并导致广泛反应性星形胶质细胞增多症的扩展。在这项研究建议中，我们结合了体内遗传建模，离体脑器官切片培养物，免疫组织化学，流式细胞术和单细胞rnasequencing 研究Treg细胞促进脑转移的建立和进展的假设调节高度异质和塑性反应性星形胶质细胞种群。拟议研究的结果将阐明脑转移性疾病的机制，并将基于很大程度上提供新的机会未开发的治疗生态位。