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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.

信号蛋白家族的膜蛋白最初被定性为轴突引导分子