Chemokine Signaling Defects in Human Immunodeficiency

人类免疫缺陷中的趋化因子信号传导缺陷

• 批准号: 7212179
• 负责人: GEORGE A DIAZ
• 金额: $ 26.44万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7212179
• 关键词: B lymphocyte; autosomal dominant trait; biological signal transduction; cell differentiation; chemokine; clinical research; cytokine receptors; enzyme linked immunosorbent assay; flow cytometry; human subject; hypogammaglobulinemia; immunodeficiency; ligands; polymerase chain reaction; toll like receptor

WHIM syndrome is an autosomal dominant disease causing hypogammaglobulinernia, congenital neutropenia, variable T cell deficiency, and an unusual predisposition to human papillomavirus infection. Molecular genetic studies in patients with the disease have localized the trait locus to chromosome 2q21 and revealed truncating mutations in the gene encoding the chemokine receptor CXCR4. Signaling through the mutant receptors was enhanced in patient-derived lymphoblastoid cells, consistent with an activating mechanism. The receptor and its ligand are well studied because of their roles in HIV cell entry during infection and in B cell development and lymphoid tissue organization. Absence of the receptor compromises early B cell survival, but lymphocyte defects in patients carrying truncated CXCR4 receptors are not simply quantitative, raising the possibility of failure to migrate to the appropriate developmental compartment and/or maturation defects. This proposal will focus on establishing the effect of truncation mutations at the level of chemotaxis, signal transduction, and beta-arrestin-mediated receptor internalization in human and genetically modified murine cells expressing mutant CXCR4 receptors. Intracellular signaling following CXCR4 activation by CXCL12 is complex, involving multiple effectors. Preliminary evidence suggests that regulation of G-protein-coupled and ERK1/2 signaling is impaired in WHIM syndrome disease cells. Biochemical analysis of signaling pathways implicated in CXCR4 signaling and chemotaxis will be performed in B cells at distinct stages of maturation. In vitro studies will be coupled to determination of the in vivo effect of CXCR4 mutations on lymphoid organ development. In addition to providing insight into the disease pathophysiology, the resulting data will provide additional information on the role of the receptor tail domain in the developmental regulation of receptor responsiveness. The proposed studies share with Project 2 of the Program Project application a focus on mechanisms of hypogammaglobulinemia in immunodeficiency diseases and the possible role of migration defects in disease pathophysiology.

WHIM 综合征是一种常染色体显性遗传疾病，可导致低丙种球蛋白血症、先天性 中性粒细胞减少症、多种 T 细胞缺乏症以及人乳头瘤病毒感染的异常倾向。 针对该疾病患者的分子遗传学研究已将性状位点定位于染色体 2q21，并揭示了编码趋化因子受体 CXCR4 的基因中的截短突变。在患者来源的淋巴母细胞中，通过突变受体的信号传导得到增强，这与激活机制一致。该受体及其配体因其在感染期间 HIV 细胞进入以及 B 细胞发育和淋巴组织组织中的作用而得到了深入研究。受体的缺失会影响早期 B 细胞的存活，但携带截短 CXCR4 受体的患者的淋巴细胞缺陷并不是简单的定量，这增加了无法迁移到适当的发育区室和/或成熟缺陷的可能性。该提案将重点研究表达突变 CXCR4 受体的人类和转基因小鼠细胞中截短突变在趋化性、信号转导和 β-抑制蛋白介导的受体内化水平上的影响。 CXCL12 激活 CXCR4 后的细胞内信号传导非常复杂，涉及多个效应器。初步证据表明，WHIM 综合征疾病细胞中 G 蛋白偶联和 ERK1/2 信号传导的调节受到损害。将在不同成熟阶段的 B 细胞中对涉及 CXCR4 信号传导和趋化性的信号传导途径进行生化分析。体外研究将与确定 CXCR4 突变对淋巴器官发育的体内影响相结合。除了提供对疾病病理生理学的深入了解外， 由此产生的数据将提供有关受体尾部结构域在 受体反应性的发育调节。拟议的研究与该计划项目申请的项目 2 共享，重点关注免疫缺陷疾病中低丙种球蛋白血症的机制以及迁移缺陷在疾病病理生理学中的可能作用。