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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.

项目总结