mTORC1 and mTORC2 selectively regulate macrophage differentiation

mTORC1 和 mTORC2 选择性调节巨噬细胞分化

• 批准号: 8389618
• 负责人: Maureen Renee Horton
• 金额: $ 19.28万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8389618
• 关键词: Alveolar Cell; Asbestosis; Autoimmunity; Automobile Driving; Bleomycin; Cell Differentiation process; Cells; Chronic; Cicatrix; Complex; Data; Development; Disease; Environment; Epithelial; Extracellular Matrix; Feedback; Fibroblasts; Fibrosis; Hamman-Rich syndrome; Healed; Homeostasis; Hyperplasia; Immune response; Infection; Inflammation; Inflammatory; Inflammatory Response; Injury; Interferons; Interleukin-13; Interleukin-4; Knock-out; Lung; Lung diseases; Malignant Neoplasms; Morbidity - disease rate; Mus; Pathologic Processes; Pathway interactions; Physiological Processes; Play; Predisposition; Protein-Serine-Threonine Kinases; Pulmonary Fibrosis; Regulatory T-Lymphocyte; Relative (related person); Resistance; Rheumatoid Arthritis; Role; Sarcoidosis; Scleroderma; Signal Transduction; T cell differentiation; T-Lymphocyte; Testing; Th2 Cells; Tissues; healing; human FRAP1 protein; immune activation; in vivo; indium-bleomycin; lung injury; macrophage; mortality; mouse model; new therapeutic target; novel; prevent; response

DESCRIPTION (provided by applicant): mTORC1 and mTORC2 selectively regulate macrophage differentiation. Rapid and robust inflammatory responses play a critical role in protecting the host against infections and environmental insults. Likewise, the early induction of negative feedback loops promotes healing and prevents autoimmunity and tissue destruction due to over exuberant responses. Chronic persistent unregulated inflammation often leads to tissue destruction by promoting the development of fibrosis. Although pulmonary fibrosis appears to be the end result of chronic unremitting immune activation, often neither the inciting agents nor the precise factors driving the fibrotic response are known. Macrophages play a crucial role in directing both host-innate and acquired immune responses. Classically activated macrophages (CAM) are induced by IFN-? or LPS and skew the immune response toward a Th1 environment. Alternatively activated macrophages (AAM) are induced by IL-4 or IL-13 and promote a Th2 environment. AAM macrophages have been implicated in both physiologic and pathologic processes such as homeostasis, inflammation, cancer and fibrosis. However, the precise role and even phenotypic definition of "alternatively activated" macrophage subsets in modulating diseases remains unclear. While it is clear that the environment influences the development of macrophages along a CAM (IFN- ?) or AAM (IL-4) pathway, the precise signaling mechanisms regulating this differentiation remains largely unknown. Recently our collaborator (Jonathan Powell) has determined that the serine/threonine kinase mTOR plays a critical role in directing T helper cell differentiation. T cells lacking mTOR complex 1 (TORC1) selectively fail to develop into Th1 and Th17 cells while T cells lacking TORC2 activity fail to develop into Th2 cells but retain their ability to become Th1 and Th17 cells. We hypothesize that similar to T cell differentiation, macrophage differentiation is also controlled by mTOR. To test this hypothesis, our lab has generated a novel mouse model in which mTOR, mTORC1, or mTORC2 are selectively knocked out in murine macrophages. Indeed our preliminary data support this hypothesis and further delineate a critical role for mTOR in macrophages in regulating the inflammation leading to pulmonary fibrosis. To this end we will test the hypothesis that mTOR plays a critical role in the development of alternatively activated macrophages and pulmonary fibrosis by pursuing the following Specific Aims: Aim 1 - mTOR regulates macrophage differentiation and Aim 2 - alternatively activated macrophages (M2) promote pulmonary fibrosis.

描述（由申请人提供）：mTORC1和mTORC2选择性调节巨噬细胞分化。快速而强烈的炎症反应在保护宿主免受感染和环境侵害方面发挥着关键作用。同样，负反馈回路的早期诱导可以促进愈合并防止由于过度旺盛的反应而导致的自身免疫和组织破坏。慢性持续性不受调节的炎症常常通过促进纤维化的发展而导致组织破坏。尽管肺纤维化似乎是长期不懈的免疫激活的最终结果，但通常既不知道刺激因素，也不知道驱动纤维化反应的确切因素。巨噬细胞在指导宿主先天性和获得性免疫反应中发挥着至关重要的作用。经典激活的巨噬细胞 (CAM) 由 IFN-α 诱导。或 LPS 并使免疫反应偏向 Th1 环境。选择性活化巨噬细胞 (AAM) 由 IL-4 或 IL-13 诱导并促进 Th2 环境。 AAM 巨噬细胞与稳态、炎症、癌症和纤维化等生理和病理过程有关。然而，“交替激活”巨噬细胞亚群在调节疾病中的确切作用甚至表型定义仍不清楚。虽然很明显环境会沿着 CAM (IFN-α) 或 AAM (IL-4) 途径影响巨噬细胞的发育，但调节这种分化的精确信号机制仍然很大程度上未知。最近，我们的合作者 (Jonathan Powell) 确定丝氨酸/苏氨酸激酶 mTOR 在指导 T 辅助细胞分化中发挥着关键作用。缺乏 mTOR 复合物 1 (TORC1) 的 T 细胞选择性地无法发育为 Th1 和 Th17 细胞，而缺乏 TORC2 活性的 T 细胞无法发育为 Th2 细胞，但保留其成为 Th1 和 Th17 细胞的能力。我们假设与 T 细胞分化类似，巨噬细胞分化也受 mTOR 控制。为了验证这一假设，我们的实验室构建了一种新型小鼠模型，其中 mTOR、mTORC1 或 mTORC2 在小鼠巨噬细胞中被选择性敲除。事实上，我们的初步数据支持了这一假设，并进一步阐明了巨噬细胞中 mTOR 在调节导致肺纤维化的炎症中的关键作用。为此，我们将通过追求以下具体目标来检验 mTOR 在替代性活化巨噬细胞和肺纤维化的发展中发挥关键作用的假设：目标 1 - mTOR 调节巨噬细胞分化，目标 2 - 替代性活化巨噬细胞 (M2) 促进肺纤维化。