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：
10631991
负责人：
Paula Daniela Bos
金额：
$ 39.65万
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/10631991
关键词：
Ablation Amphiregulin Applications Grants Astrocytes Bone Marrow Bone Marrow Neoplasms Brain Brain Neoplasms CCL2 gene Cancer Patient Cell Line Cell physiology Cells Central Nervous System Cephalic Development Disease Encephalitis Epidermal Growth Factor Receptor Event FOXP3 gene Flow Cytometry Fright Genetic Models Gliosis Goals Growth Heterogeneity Image Immune response Immunofluorescence Immunologic Immunohistochemistry Infiltration Interferons Lesion Light Malignant Neoplasms Mediating Metastasis Induction Metastatic malignant neoplasm to brain Modeling Neoplasm Metastasis Neurologic Symptoms Neurons Outcome Pathology Pathway interactions Patients Plasminogen Activator Play Population Primary Neoplasm Process Production Prognosis Reactive Inhibition Regulatory T-Lymphocyte Research Proposals Resistance Role STAT3 gene Signal Transduction Slice Systemic Therapy Therapeutic Time Tissues Tumor Burden astrogliosis brain tissue calcium absorption 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.

项目概要该拨款提案的主要目标是研究调节性 T (Treg) 细胞和脑转移性疾病背景下的反应性星形胶质细胞增生及其对脑转移过程的影响。脑转移代表癌症的最后阶段，可用的治疗方法非常有限。不可避免地，脑转移患者会在很短的时间内死于疾病。初期有很强的阻力脑转移的发展和星形胶质细胞的激活是观察到的最早事件之一在脑损伤建立期间。它们的双重作用首先反对然后有利于脑转移进展情况才刚刚开始被研究。 Treg 细胞在发炎的脑组织中定殖并扩张，并且已被证明可以抑制中风模型中的反应性神经胶质增生。我们已经证明 Treg 细胞消融在早期和晚期脑转移中，脑肿瘤负荷显着减少，并导致广泛的反应性星形胶质细胞增多症的扩张。在这项研究提案中，我们结合了体内遗传模型，离体脑器官切片培养、免疫组织化学、流式细胞术和单细胞 RNA 测序研究 Treg 细胞通过以下方式促进脑转移的建立和进展的假设：调节高度异质性和可塑性反应性星形胶质细胞群。拟议研究的结果将阐明脑转移性疾病的机制，并将提供基于很大程度上的新机会未经探索的治疗利基。