Beta-2 adrenergic signaling in immune homeostasis and reconstitution

免疫稳态和重建中的 Beta-2 肾上腺素能信号传导

• 批准号: 10610471
• 负责人: Xuefang Cao
• 金额: $ 76.6万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-15 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10610471
• 关键词: Adrenal Medulla; Adrenergic Agents; Adrenergic Agonists; Allogenic; Autoimmune Diseases; Biological Assay; Bone Marrow; Bone Marrow Cells; CSF1R gene; Cell Count; Cell Differentiation process; Cell physiology; Cells; Clinical Trials; Collaborations; Complex; Cre-LoxP; Cytometry; Dendritic Cells; Development; Disease; Epinephrine; Flow Cytometry; Functional disorder; Genes; Genetic Polymorphism; Genus Hippocampus; Hematological Disease; Hematopoietic Neoplasms; Homeostasis; Hormones; Host Defense; Human; Immune; Immune System Diseases; Immune response; Immune signaling; Immune system; Immunotherapy; Intervention; Knock-out; Ligands; Link; Macrophage; Macrophage Colony-Stimulating Factor; Mature T-Lymphocyte; Metabolic; Modeling; Molecular; Mus; Myelogenous; Myeloid Cells; Natural Immunity; Nervous System; Neuroimmune; Neurons; Neurotransmitters; Norepinephrine; Organ; Outcome; Pathogenesis; Patients; Peripheral; Phenotype; Play; Proliferating; Publishing; Receptor Signaling; Regulation; Reporting; Research; Role; Signal Pathway; Signal Transduction; Sympathetic Nervous System; System; T cell differentiation; T cell reconstitution; T cell response; T-Cell Depletion; T-Cell Development; T-Lymphocyte; T-Lymphocyte Subsets; Technology; Testing; Therapeutic; Thymus Gland; Transplantation; adaptive immunity; antagonist; beta-2 Adrenergic Receptors; blood treatment; cell type; germ free condition; graft vs host disease; hematopoietic cell transplantation; immune reconstitution; improved; metabolic fitness; migration; monocyte; mouse model; myeloid cell development; peripheral lymphoid organ; pharmacologic; reconstitution; restraint; transcriptome sequencing; transcriptomics; translational potential

Project Summary Neurotransmitters and hormones serve as a link between the nervous and immune systems. Among them, norepinephrine and epinephrine are synthesized in the postganglionic neurons of the sympathetic nervous system and the adrenal medulla. Upon release, they engage the β2-adrenergic receptor (β2AR) expressed on immune cells. Notably, β2AR abnormal expression and gene polymorphisms are associated with several types of autoimmune diseases. However, mechanisms by which β2AR signaling dysfunction contribute to these diseases remain largely unknown. In this context, our studies with mouse models have uncovered previously unappreciated major dichotomous roles of β2AR in immune development and reconstitution: 1) Under specific pathogen free (SPF) condition, β2AR deficiency causes significantly reduced T cell development in thymus in contrast to increased CD115+ myeloid cell development in bone marrow (BM); 2) Both thymic and myeloid development phenotypes are remarkably more manifested during immune reconstitution following allogeneic hematopoietic cell transplantation (allo-HCT); 3) β2AR plays differential roles in in mature peripheral T cell subsets and myeloid cell subsets that result in different outcome in graft-versus-host disease (GVHD). Together, these findings highlight the critical and fundamental role of β2AR signaling in maintaining immune homeostasis and regulating immune response. Therefore, this study will pursue three specific aims to test an overarching hypothesis that β2AR signaling regulates immune development and reconstitution via cross-talking with canonical immune signaling pathways and/or fine-tuning metabolic fitness of immune cells. Aim 1 will determine mechanisms by which β2AR signaling regulates T cell development, reconstitution and GVHD. Aim 2 will define mechanisms by which β2AR signaling regulates CD115+ myeloid cell development, reconstitution and GVHD. Aim 3 will study the translational potential and mechanisms of pharmacologic β2AR intervention. We will use unbiased RNA-seq transcriptomic approach along with flow cytometry, CyTOF mass cytometry and Seahorse metabolic assay combined with cell type-specific β2AR knockout (Cre-LoxP) to define the molecular mechanisms for T cell and myeloid cell differentiation and function. In the setting of allo-HCT, we will also examine the impact of these mechanisms on GVHD and GVT effect. This project will not only improve our understanding of the fundamental mechanisms of β2AR signaling in adaptive and innate immune cells in central and peripheral immune organs, but it may also explain how β2AR signaling contributes to immunologic disorders and allo-HCT based immunotherapy. Therefore, this study may have important ramifications on therapeutic rationale based upon manipulation of β2AR signaling. Since β2AR agonists and antagonists are already widely available, new clinical trials emanating from this research could be rapidly implemented for patients receiving allo-HCT for treatment of blood cancers, or other hematologic or immunologic diseases in which allo-HCT can be curative.

项目摘要 神经递质和激素是神经和免疫系统之间的联系。 去甲肾上腺素和肾上腺素是在交感神经的后nglionic神经元中合成的 系统和肾上腺髓质。 免疫细胞，β2AR异常表达和基因多态性 但是，自身免疫性疾病。 在这种情况下，疾病仍然很大。 在特定的情况下，β2AR在免疫发育和重构中的特定未批准的主要二分法作用：1） 病原体无病原体（SPF）条件，β2AR缺乏症会显着降低胸腺的胸腺。 与骨髓中CD115+髓样细胞发育的增加（BM）形成对比； 在免疫重组过程中，开发表型更明显地表现出来 造血细胞移植（Allo-HCT）; 3）β2AR在成熟的周围T细胞中起差异作用 子集和髓样细胞子集导致移植物抗宿主疾病（GVHD）的不同结果。 这些发现突出了β2AR信号在维持免疫稳态中的关键和基本作用 并调节免疫反应。 假设β2AR信号传导通过与With with with tways进行交叉言行调节免疫发育和重新分配。 规范的免疫信号通路和/或免疫细胞的微调代谢适应性。 β2AR信号调节t -cell发育，重新构造和GVHD的机制将定义 β2AR信号传导调节CD115+髓样细胞发育，重构和GVHD的机制。 AIM 3将研究我们将使用药理学β2AR的转化潜力和机制 无偏的RNA-SEQ转录组方法以及流式细胞仪，质量细胞术和海马 代谢测定与细胞类型特异性β2AR基因敲除（CRE-LOXP）结合来定义分子机制 对于T细胞和髓样细胞的区分和功能，我们还将检查影响 这些关于GVHD和GVT效应的机制。 中央和周围的自适应和先天免疫细胞中β2AR信号传导的基本机制 免疫器官，但它也可以解释β2AR信号如何有助于免疫学和Allo-HCT 基于免疫疗法。 在操纵β2AR信号后。 从研究杯中发出的临床试验，对于接受Allo-HCT的患者迅速显示出来？ 血液癌或其他血液学或免疫疾病的治疗可以治愈。