Molecular Basis of Hyper lgE Immunodeficiency

高 lgE 免疫缺陷的分子基础

• 批准号: 7758764
• 负责人: Talal Amine Chatila
• 金额: $ 34.57万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7758764
• 关键词: Address; Allergic; Allergic inflammation; Antibody Formation; Antigens; Apoptotic; Asthma; Attenuated; B-Lymphocytes; Binding; Cell Culture Techniques; Chronic; Enhancing Antibodies; Epithelial Cells; Event; Evolution; Gene Targeting; Genes; Genetic Polymorphism; Goblet Cells; ITIM; Immunologic Deficiency Syndromes; Inflammatory Response; Interleukin 4 Receptor; Interleukin-13; Interleukin-4; Intervention; Knock-in Mouse; Ligands; Mediating; Medical; Memory; Metaplasia; Microarray Analysis; Molecular; Mus; Mutagenesis; Mutant Strains Mice; Mutation; Phenylalanine; Play; Receptor Signaling; Regulation; Role; Signal Pathway; Signal Transduction; Specificity; Stream; Testing; Tissues; Transgenic Animals; Tyrosine; airway hyperresponsiveness; allergic airway inflammation; base; in vivo; mutant; novel; response; transcription factor

The interleukin 4 receptor alpha chain (IL-4Ra) plays a key role in allergic inflammatory responses. However, whereas the function of its dedicated transcription factor Stat6 in promoting allergic inflammation is well established, those of the other two signaling branches down-stream of the IL-4Ra I4R and ITIM motifs remains unclear. By employing a targeted gene knock-in approach that inactivated the I4R motif by mutagenesis of its effector tyrosine residue into phenylalanine (Y500F), we have demonstrated novel tissue and ligand-specific functions of this motif. The Y500F mutation enhanced antigen-driven antibody responses and allergic airway inflammation, consistent with a negative regulatory function of the I4R motif in receptor signaling. Remarkably however, I4R mutagenesis selectively impaired two cardinal effects of DL-13 on resident airway tissues, including induction of airway hyper-responsiveness (AHR) and metaplasia of primary tracheal epithelial cell cultures into goblet cells, while sparing the induction of the same events by IL-4. To examine the mechanism of enhanced antibody response in Y500F mutants, we propose to test the hypothesis that the I4R motif down-regulates DL-4Ra signaling in B cells and identify the molecular basis of this function. To probe the function of the I4R motif in IL-13 signaling in resident airway tissues, we propose to examine the hypothesis that signaling via the I4R motif mediates key EL-13 responses in airway epithelial cells relevant to AHR and goblet cell metaplasia, and that it mediates aspects of IL-13-dependent chronic structural airway changes. Finally, we propose to employ newly derived mice in which the ITIM motif has been inactivated by mutagenesis of its effector tyrosine residue (Y709F) to address the in vivo function of this motif in IL-4Ra signaling and allergic inflammation. These studies will identify fundamental regulatory mechanisms involved in allergic inflammation and help devise targeted interventions in related medical conditions including asthma.

白介素4受体α链（IL-4RA）在过敏性炎症中起关键作用 回答。但是，尽管其专用转录因子STAT6的功能 促进过敏性炎症已经很好地确定，其他两个信号传导的炎症 IL-4RA I4R和ITIM图案的分支下游仍不清楚。经过 采用针对性的基因敲入方法，通过 其效应子酪氨酸残基到苯丙氨酸（Y500F）的诱变，我们有 展示了该基序的新组织和配体特异性功能。 Y500F 突变增强了抗原驱动的抗体反应和过敏性气道炎症， 与I4R基序在受体信号传导中的负调控功能一致。 但是，I4R诱变有选择地损害了DL-13的两个基本效应 在常驻气道组织上，包括诱导气道高反应性（AHR） 一级气管上皮细胞培养在杯状细胞中的转移，同时保留 IL-4诱导相同事件。检查增强的机制 Y500F突变体中的抗体反应，我们建议测试I4R基序的假设 下调B细胞中的DL-4RA信号传导，并确定其分子基础 功能。探测居民气道IL-13信号中I4R基序的功能 组织，我们建议检查以下假设 气道上皮细胞中的关键EL-13响应与AHR和Goblet细胞化生有关， 并且它介导了IL-13依赖性慢性结构气道的变化。 最后，我们建议采用新衍生的小鼠，其中ITIM图案已成为 由于其效应酪氨酸残基（Y709F）的诱变而灭活以解决体内 该基序在IL-4RA信号传导和过敏性炎症中的功能。这些研究会 确定涉及过敏性炎症和帮助的基本调节机制 在包括哮喘在内的相关医疗状况中设计有针对性的干预措施。

项目成果

CaMKIV/Gr is dispensable for spermatogenesis and CREM-regulated transcription in male germ cells.

• DOI: 10.1152/ajpendo.2001.281.5.e931
• 发表时间: 2001-11
• 期刊: American journal of physiology. Endocrinology and metabolism
• 作者: F. Blaeser;J. Toppari;M. Heikinheimo;W. Yan;M. Wallace;N. Ho;T. Chatila

Critical function of the CD40 pathway in parvovirus B19 infection revealed by a hypomorphic CD40 ligand mutation.

CD40 配体亚态突变揭示了细小病毒 B19 感染中 CD40 通路的关键功能。

• DOI: 10.1016/j.clim.2005.08.005
• 发表时间: 2005
• 期刊: Clinical immunology (Orlando, Fla.)
• 作者: Blaeser,Frank;Kelly,Michael;Siegrist,Karen;Storch,GregoryA;Buller,RichardS;Whitlock,Jessica;Truong,Nga;Chatila,TalalA
• 通讯作者: Chatila,TalalA