Role of Semaphorin 4A in Allergic Inflammation

Semaphorin 4A 在过敏性炎症中的作用

基本信息

批准号：
10455489
负责人：
Achsah D. Keegan
金额：
$ 38.63万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10455489
关键词：
Acute Address Allergens Allergic Allergic inflammation Amino Acids Asthma Binding Blocking Antibodies Bone Marrow CD100 antigen Cell Line Cell Surface Proteins Cells Chimera organism Chronic Correlation Studies Data Dendritic Cells Disease Epithelial Cells Equilibrium Experimental Autoimmune Encephalomyelitis Family Flow Cytometry Generations Genes Goals Howard Temin Award Human Hyperplasia Image In Vitro Infiltration Inflammation Inflammatory Response Inhalation Integral Membrane Protein Interleukin-13 Knowledge Lymphocyte Activation Malignant Neoplasms Membrane Proteins Mus Mutagenesis Neuroimmune Ovalbumin Pathologic Phenotype Physiological Play Process Pulmonary Inflammation Recombinants Regulatory T-Lymphocyte Research Research Project Grants Research Proposals Role SEMA3F gene Semaphorins Severity of illness Signal Transduction Statistical Data Interpretation Stream Symptoms T cell differentiation T cell response T cell therapy T-Cell Activation T-Lymphocyte Testing Therapeutic Western Blotting Wild Type Mouse Work airway hyperresponsiveness allergic airway inflammation angiogenesis antigen-specific T cells axon guidance base bronchial epithelium cell type experimental study in vitro Assay in vivo in vivo evaluation member mutant neuron development novel therapeutic intervention plexin receptor response

项目摘要

The semaphorin family of membrane proteins was initially characterized as axon-guidance molecules criti- cal for neuronal development. It is now recognized that they play critical roles in a number of physiological and pathologic responses including angiogenesis, cancer, and inflammation by binding to a diverse array of counter receptors. Recent studies suggest that semaphorins can act as co-stimulatory molecules. Se- ma4A was previously shown to be an important co-stimulatory molecule for T-cell activation in vitro and for Th1-inflammation in vivo. Sema4A was shown to control the Th1/Th2 balance. However, we recently demonstrated that Sema4A played a down-regulatory role during allergic (Type II) inflammation in vivo. We observed increased allergic airway inflammation accompanied by increased IL-13 and lower Treg numbers in allergen-treated Sema4A-/- mice compared to WT mice. Interestingly, allergic inflammation was significantly reduced in either WT or Sema4A-/- mice by administration of recombinant soluble Se- ma4A. Based on these results, we propose that Sema4A is a negative regulator of Th2-driven responses. However, the mechanism by which Sema4A dampens allergic inflammation is unknown, representing a significant gap in knowledge. Thus, the overall goal of this research proposal is to determine the mecha- nism by which Sema4A limits allergic inflammation. Based on our preliminary data, we hypothesize that Sema4A limits allergic inflammation through interaction with Plexin-B1 to enhance the numbers and activi- ty of Tregs. This hypothesis will be tested by completing the following specific aims: 1) to characterize the contribution of Sema4A / Plexin B1 interaction in the control of T cell responses in allergic lung inflamma- tion, 2) to evaluate the contribution of Plexin B1 to the suppressive activity of Sema4A in vivo, and 3) to delineate the critical amino acids responsible for Sema4A interaction with Plexin B1. Our research has significant potential to identify novel therapeutic strategies to treat allergic inflammation.

膜蛋白信号蛋白家族最初被定性为轴突引导分子 cal 用于神经元发育。现在人们认识到它们在许多生理学中发挥着关键作用通过与不同的阵列结合而产生病理反应，包括血管生成、癌症和炎症反受体。最近的研究表明，信号蛋白可以充当共刺激分子。硒- ma4A 先前被证明是体外 T 细胞激活的重要共刺激分子 Th1-体内炎症。 Sema4A 被证明可以控制 Th1/Th2 平衡。然而，我们最近证明 Sema4A 在体内过敏（II 型）炎症期间发挥下调作用。我们观察到过敏性气道炎症增加，并伴有 IL-13 增加和 Treg 降低与 WT 小鼠相比，经过敏原处理的 Sema4A-/- 小鼠的数量。有趣的是，过敏性炎症通过施用重组可溶性 Se-，WT 或 Sema4A-/- 小鼠中的 ma4A。基于这些结果，我们提出 Sema4A 是 Th2 驱动反应的负调节因子。然而，Sema4A 抑制过敏性炎症的机制尚不清楚，这代表了一种知识上的重大差距。因此，本研究提案的总体目标是确定机械 Sema4A 限制过敏性炎症的机制。根据我们的初步数据，我们假设 Sema4A 通过与 Plexin-B1 相互作用来限制过敏性炎症，以增强数量和活性 Tregs 的数量。该假设将通过完成以下具体目标进行检验：1）表征 Sema4A / Plexin B1 相互作用在控制过敏性肺炎症 T 细胞反应中的贡献化，2) 评估 Plexin B1 对体内 Sema4A 抑制活性的贡献，以及 3) 描述了负责 Sema4A 与 Plexin B1 相互作用的关键氨基酸。我们的研究在确定治疗过敏性炎症的新治疗策略方面具有巨大潜力。