Regulation of Interleukin-5 Receptor Signaling

IL-5 受体信号传导的调节

• 批准号: 6650360
• 负责人: MAGARITA MARTINEZ-MOCZYGEMBA
• 金额: $ 10.8万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6650360
• 关键词: biological signal transduction; colony stimulating factor; cytokine receptors; eosinophil; eosinophilia; gene mutation; genetically modified animals; hypersensitivity; interleukin 3; interleukin 5; laboratory mouse; phosphorylation; proteasome; protein degradation; protein kinase; serine; site directed mutagenesis; tyrosine; ubiquitin

DESCRIPTION (provided by applicant): Dr. Martinez-Moczygemba is a postdoctoral fellow whose research interest is to identify the molecular events mediating interleukin-5 (IL-5)-induced signal termination. Understanding these mechanisms should provide novel targets for the modulation of IL-5-mediated inflammatory responses such as allergic inflammation and asthma. The Research Scholar Development Award (K22) will aid Dr. Martinez-Moczygemba to accomplish her research goals as well as to attain a tenure-track assistant professor appointment. IL-5 specifically promotes the differentiation and survival of eosinophils and is critical to the pathobiology of eosinophilic inflammation in allergic disorders and asthma. IL-5 initiates its cellular effects by binding to a heterodimeric IL-5 receptor leading to the activation of the JAK!STAT, Ras/MAPK, and the PI3 kinase signaling pathways. The goal of this proposal is to delineate the molecular events that initiate, mediate, and modulate termination of IL-5 signal transduction. Aim I. Elucidate the molecular events that initiate proteasome termination of IL-5-induced signal transduction. We will determine if tyrosine or serine phosphorylation of betac is required for its proteasomal degradation by using specific inhibitors of these kinases, as well as making site-directed mutants of these beta-c phosphorylation sites. We will also determine if beta-c ubiquitination is necessary for its proteasomal degradation. Aim 2. Investigate the molecular mechanisms that mediate endocytosis and lysosomal degradation of the full length and truncated IL-5R following IL-5 stimulation. Potential endocytic consensus sequences in the cytoplasmic domains of beta-c and IL-5R-alpha will be evaluated for their role in ligand-induced endocytosis of the full-length receptors by targeted deletions and by site-directed mutagenesis. Aim 3. Determine if other shared cytokine signaling receptor chains are proteasomally-regulated. Other shared signaling receptor chains such as gamma- c / IL-4R-alpha will be analyzed for their susceptibility to degradation by proteasomes following ligand stimulation. Aim 4. Demonstrate the physiologic consequence of cytokine-induced heterotypic desensitization of beta-c receptors in vivo. GM-CSF and IL-3 over-expressing transgenic mice will be evaluated for their ability to develop eosinophilia following treatment with high doses of IL-5. In addition, eosinophils from IL-5 transgenic mice will be isolated and analyzed for their ability to be further stimulated by GM-CSF or IL-3 in vitro.

描述（由申请人提供）：Martinez-Moczygemba 博士是一名博士后 研究员，其研究兴趣是确定介导的分子事件 白细胞介素 5 (IL-5) 诱导的信号终止。了解这些 机制应为 IL-5 介导的调节提供新的靶点 炎症反应，例如过敏性炎症和哮喘。研究 学者发展奖（K22）将帮助 Martinez-Moczygemba 博士完成 她的研究目标以及获得终身教授助理教授 预约。 IL-5特异性促进细胞的分化和存活 嗜酸性粒细胞，对嗜酸性粒细胞炎症的病理学至关重要 过敏性疾病和哮喘。 IL-5 通过以下方式启动其细胞作用： 与异二聚体 IL-5 受体结合，导致激活 JAK!STAT、Ras/MAPK 和 PI3 激酶信号通路。此举的目标 提议是描述启动、介导和调节的分子事件 调节 IL-5 信号转导的终止。目标 I. 阐明 启动蛋白酶体终止 IL-5 诱导信号的分子事件 转导。我们将确定 betac 的酪氨酸或丝氨酸是否磷酸化 其蛋白酶体降解需要使用特定的抑制剂 这些激酶，以及制作这些 β-c 的定点突变体 磷酸化位点。我们还将确定 beta-c 泛素化是否是 其蛋白酶体降解所必需的。目标 2. 研究分子 介导全细胞内吞作用和溶酶体降解的机制 IL-5刺激后的长度和截短的IL-5R。潜在的内吞作用 β-c 和 IL-5R-α 细胞质结构域中的共有序列将 评估它们在配体诱导的全长内吞作用中的作用 通过定向删除和定点诱变来识别受体。目标3。 确定其他共享的细胞因子信号传导受体链是否 蛋白酶体调节。其他共享信号受体链，例如γ- c / IL-4R-alpha 将通过以下方式分析其降解敏感性 配体刺激后的蛋白酶体。目标 4. 展示生理学 细胞因子诱导的β-c异型脱敏的结果 体内受体。 GM-CSF 和 IL-3 过表达转基因小鼠将 评估他们在治疗后出现嗜酸性粒细胞增多的能力 高剂量的IL-5。此外，来自IL-5转基因小鼠的嗜酸性粒细胞将被 分离并分析其被 GM-CSF 进一步刺激的能力或 IL-3 体外。