mTORC1 and mTORC2 selectively regulate macrophage differentiation

mTORC1 和 mTORC2 选择性调节巨噬细胞分化

• 批准号: 8223936
• 负责人: Maureen Renee Horton
• 金额: $ 24.3万
• 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 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8223936
• 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. PUBLIC HEALTH RELEVANCE: Pulmonary fibrosis is a devastating disease associated with significant morbidity and mortality. Alternatively activated macrophages have been associated with pulmonary fibrosis, though their exact role in this disease is unknown. By studying the role of mTOR in the differentiation of macrophages, we hope to identify new therapeutic targets.

描述（申请人提供）：mTORC 1和mTORC 2选择性调节巨噬细胞分化。快速和强烈的炎症反应在保护宿主免受感染和环境侵害方面起着关键作用。同样，负反馈回路的早期诱导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通常通过促进纤维化的发展而导致组织破坏。虽然肺纤维化似乎是慢性持续免疫激活的最终结果，但通常既不知道激发剂，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应答中起着至关重要的作用。经典激活的巨噬细胞（CAM）诱导IFN-？或LPS并使免疫应答偏向Th 1环境。另外，活化的巨噬细胞（AAM）由IL-4或IL-13诱导并促进Th 2环境。AAM巨噬细胞参与生理和病理过程，如稳态、炎症、癌症和纤维化。然而，在调节疾病中的“交替激活”巨噬细胞亚群的确切作用甚至表型定义仍不清楚。虽然很明显，环境影响巨噬细胞沿着CAM（IFN-？）或AAM（IL-4）途径，但调节这种分化的精确信号传导机制在很大程度上仍然未知。最近，我们的合作者（Jonathan Powell）已经确定丝氨酸/苏氨酸激酶mTOR在指导T辅助细胞分化中起关键作用。缺乏mTOR复合物1（TORC 1）的T细胞选择性地不能发育成Th 1和Th 17细胞，而缺乏TORC 2活性的T细胞不能发育成Th 2细胞，但保留它们成为Th 1和Th 17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，我们的实验室已经产生了一种新的小鼠模型，其中mTOR，mTORC 1或mTORC 2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这一假设，并进一步描绘了巨噬细胞中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特定目标来检验mTOR在交替激活的巨噬细胞和肺纤维化的发展中起关键作用的假设：Aim 1 - mTOR调节巨噬细胞分化，Aim 2 -交替激活的巨噬细胞（M2）促进肺纤维化。 公共卫生相关性：肺纤维化是一种与显著发病率和死亡率相关的毁灭性疾病。替代活化的巨噬细胞与肺纤维化有关，尽管它们在这种疾病中的确切作用尚不清楚。通过研究mTOR在巨噬细胞分化中的作用，我们希望找到新的治疗靶点。