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疾病，导致先天性降低症 中性粒细胞减少症，可变细胞缺乏症以及对人乳头瘤病毒感染的异常易感性。 该疾病患者的分子遗传研究将特征基因座定位于2q21染色体，并揭示了编码趋化因子受体CXCR4的基因中的截断突变。在患者衍生的淋巴母细胞细胞中，通过突变受体的信号增强了与激活机制一致的信号。该受体及其配体在感染期间在HIV细胞进入以及B细胞发育和淋巴组织组织中的作用进行了充分的研究。缺乏受体会损害早期B细胞的存活，但是携带截短CXCR4受体的患者的淋巴细胞缺陷并不是简单的定量，这增加了未能迁移到适当的发育室和/或成熟缺陷的可能性。该建议将着重于在人类和表达突变的CXCR4受体的趋化症和遗传修饰的鼠类细胞中建立趋化性，信号转导和β-arrestin介导的受体内在化的截短突变的影响。 CXCL12激活CXCR4后的细胞内信号传导很复杂，涉及多个效应子。初步证据表明，在综合症综合症细胞中，G蛋白偶联和ERK1/2信号的调节受损。与CXCR4信号传导和趋化性有关的信号通路的生化分析将在B细胞中在不同的成熟阶段进行。体外研究将耦合，以确定CXCR4突变对淋巴器官发育的体内效应。除了提供有关疾病病理生理学的见解之外， 结果数据将提供有关受体尾域在 受体反应的发展调节。拟议的研究与计划项目应用的项目2共享，重点是免疫缺陷疾病中低磁性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。