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系统和免疫系统之间的联系。他们之中， 去甲肾上腺素和肾上腺素是在交感神经后神经元中合成的 系统和肾上腺髓质。释放后，它们参与了在上表达的β2-肾上腺素能受体（β2AR） 免疫细胞。值得注意的是，β2AR异常表达和基因多态性与几种类型有关 自身免疫性疾病。但是，β2AR信号传导功能障碍有助于这些机制 疾病在很大程度上仍然未知。在这种情况下，我们对鼠标模型的研究以前已经发现了 β2AR在免疫发展和重建中的未批准的主要二分法：1） 病原体无病原体（SPF）条件，β2AR缺乏会显着降低胸腺中T细胞的发育 与骨髓（BM）中CD115+髓样细胞发育的增加形成对比； 2）胸腺和髓样 在同种异体后，在免疫重建过程中，开发表型更明显地表现出来 造血细胞移植（Allo-HCT）； 3）β2AR在成熟的外围T细胞中扮演鉴别作用 子集和髓样细胞子集导致移植物抗宿主病（GVHD）的结果不同。一起， 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。因此，这项研究将追求三个特定的目标，以测试总体 假设β2AR信号传导通过与 典型的免疫信号通路和/或免疫细胞的微调代谢适应性。 AIM 1将确定 β2AR信号传导调节T细胞发育，重构和GVHD的机制。 AIM 2将定义 β2AR信号传导调节CD115+髓样细胞发育，重建和GVHD的机制。 AIM 3将研究药物Cologicβ2AR干预的翻译潜力和机制。我们将使用 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 用于T细胞和髓样细胞的分化和功能。在Allo-HCT的环境中，我们还将检查影响 这些关于GVHD和GVT效应的机制。这个项目不仅会提高我们对 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信号传导如何促进免疫疾病和Allo-HCT 基于免疫疗法。因此，这项研究可能对基于治疗的理由有重要的影响 操纵β2AR信号传导后。由于β2AR激动剂和拮抗剂已经广泛使用，因此 可以迅速实施这项研究的临床试验 血液癌或其他血液学或免疫疾病的治疗可以治愈。