The biological effect and the mode of action of the CXCL7-CXCL12 chemokine heterodimer

CXCL7-CXCL12趋化因子异二聚体的生物学效应和作用方式

基本信息

批准号：
10730914
负责人：
Irina V Nesmelova
金额：
$ 46.2万
依托单位：
UNIVERSITY OF NORTH CAROLINA CHARLOTTE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10730914
关键词：
Adhesions Affect Atherosclerosis Autoimmune Diseases Award Binding Biological Biological Assay Biology Biophysics Blood Platelets CXCR4 Receptors CXCR4 gene Cell Migration Induction Cell surface Cells Development Disease Disulfides Endothelium Environment Future G-Protein-Coupled Receptors Glycosaminoglycans HIV/AIDS Health Heterodimerization Homo Human IL8RB gene Individual Infection Institution Interleukin-8B Receptor Intervention Knowledge Malignant Neoplasms Mediating Methods Molecular Nature Outcome PPBP gene Public Health Regulation Research Role Signal Induction Signal Transduction Stromal Cell-Derived Factor 1 Wages Western Blotting cell motility chemokine graduate student in vivo insight intermolecular interaction migration monomer neutrophil novel therapeutic intervention response screening structural biology training opportunity undergraduate student

项目摘要

ABSTRACT Chemokines are essential in health and disease such as infections, autoimmune diseases, atherosclerosis, HIV/AIDS, and cancer. Many chemokines engage in heterophilic interactions with each other to form heterodimers, leading to synergistic activity enhancement or reduction dependent on the nature of heterodimer- forming chemokines. The mode of action of chemokine heterodimers remains poorly understood. Previously, we identified all platelet-derived chemokines interacting with the two most abundant platelet chemokines, CXCL4 and CXCL7. The CXCL12 chemokine demonstrated strong heterodimerization with CXCL7. In the current project, we will determine the biological consequences of these new interactions and the mode of action of the CXCL7-CXCL12 heterodimer. In aim 1, we will determine the effect of CXCL7-CXCL12 heterodimerization on CXCL12-mediated activities, that the CXCL7-CXCL12 heterodimer binds and activates the CXCL12’s receptor CXCR4, and the molecular mechanism underlying the effect of the CXCL12-based heterodimers on cell migration. In aim 2, we will determine the effect of CXCL7-CXCL12 heterodimerization on CXCL7-mediated activities (neutrophil adhesion and migration) and the involvement of the CXCR2 receptor in CXCL7-CXCL12 heterodimer-mediated activities. The results of this project will deepen our understanding of chemokine biology and inform the future development of novel therapeutic intervention strategies exploiting heterophilic chemokine interactions.

抽象的趋化因子对于健康和疾病至关重要，例如感染、自身免疫性疾病、动脉粥样硬化、 HIV/艾滋病和癌症许多趋化因子相互作用形成异嗜性。异二聚体，导致协同活性增强或降低，具体取决于异二聚体的性质以前，我们对趋化因子异二聚体的作用方式仍知之甚少。确定了与两种最丰富的血小板趋化因子 CXCL4 相互作用的所有血小板衍生趋化因子目前，CXCL12 趋化因子与 CXCL7 表现出强烈的异二聚化。项目中，我们将确定这些新相互作用的生物学后果以及作用方式 CXCL7-CXCL12 异二聚体在目标 1 中，我们将确定 CXCL7-CXCL12 异二聚体对的影响。 CXCL12 介导的活性，即 CXCL7-CXCL12 异二聚体结合并激活 CXCL12 受体 CXCR4，以及基于CXCL12的异二聚体对细胞影响的分子机制在目标 2 中，我们将确定 CXCL7-CXCL12 异二聚化对 CXCL7 介导的影响。 CXCR2 受体在 CXCL7-CXCL12 中的活性（中性粒细胞粘附和迁移）和参与该项目的结果将加深我们对趋化因子生物学的理解。并为利用异嗜趋化因子的新型治疗干预策略的未来发展提供信息互动。