Sprouty-2 Regulation of Signaling in Asthma

Sprouty-2 哮喘信号传导的调节

基本信息

批准号：
8630180
负责人：
Rafeul Alam
金额：
$ 39.63万
依托单位：
NATIONAL JEWISH HEALTH
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-15 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8630180
关键词：
Abbreviations Address Affect Allergens Asthma CD28 gene CD3 Antigens CD4 Positive T Lymphocytes Cell Differentiation process Cell Proliferation Cells Chronic Chronic Disease Clinical Defect Development Disease Down-Regulation Endocytosis Epithelial Cells Extrinsic asthma Feedback Human Impairment In Vitro Inflammation Inflammatory Knock-out Knockout Mice Knowledge Ligands MAPK3 gene Maintenance Mediating Modeling Mus Outcome Output Patients Phenotype Play Public Health Recycling Regulation Reporting Resolution Role Signal Pathway Signal Transduction Signaling Molecule T-Lymphocyte Testing Th2 Cells Tissues Up-Regulation airway hyperresponsiveness airway inflammation anergy asthmatic patient base cell motility cytokine in vivo mouse model new therapeutic target novel prevent public health relevance receptor response signal processing ubiquitin ligase

项目摘要

Abstract Asthma is a chronic inflammatory disease of the airways where T cells manifest a biased Th2/Th17 differentiation and a hyperactive phenotype. The latter is associated with sustained intracellular signaling. Signaling processes are usually transient due to negative homeostatic regulation. There is a knowledge gap in our understanding of mechanisms that induce sustained signaling. We propose to delineate the mechanism of induction of sustained signaling in T cells from asthma. We have reported that the signaling molecule sprouty 2 (spry 2) plays an essential role in establishing a self-sustained signaling mechanism for ERK1/2. To address this further we have generated CD4 targeted spry 2 knockout mice. Spry2-/- T cells have increased Cbl-b and decreased Nedd4. The foregoing ubiquitin ligases antagonistically regulate TCR ubiquitylation, endocytosis, degradation and thereby, control TCR signaling output. As a consequence of these receptor proximal abnormalities spry2-/-T cells have impaired signaling and proliferation. These impairments become more pronounced following CD28 engagement. Spry2-/- T cells have impaired Th2/Th17 differentiation. They are unable to mount airway inflammation, hyperreactivity and remodeling in a mouse model of asthma. Based upon these preliminary results we hypothesize that spry 2 amplifies and prolongs T cell signaling by forming a tripartite regulatory network where spry 2 and Nedd4 antagonize the signal terminating action of Cbl-b. Spry2- driven amplification and sustenance of signaling is important for co-stimulation, Th2/Th17 differentiation and development of asthma. Under specific aim 1 we will examine the role of spry 2 in generating sustained signaling in T cells. We will define the scope of CD3- and especially CD28-induced signaling pathways that are regulated by spry 2. We will examine the contribution of Cbl-b and Nedd4 to the spry2 knockout phenotype. Specific aim 2 will study the importance of spry 2 for Th2 and Th17 cell differentiation in vitro and in vivo in spry2-/- mice. We will delineate the signaling mechanism by which spry 2 regulates Th2/Th17 differentiation. Under specific aim 3 we will delineate the role of spry 2 in inducing and sustaining inflammation in a mouse model of chronic asthma. We will examine if Cbl-b knockout reverses the spry2 knockout phenotype. Under specific aim 4 we will study the expression of spry 2 in CD4 T cells from asthmatic patients and examine its contribution to the hyperactive T cell phenotype and biased differentiation in asthma. These studies are important because they have uncovered a hitherto unknown regulatory network involving spry2, Cbl-b and Nedd4, which controls Th2/Th17 differentiation and development of asthma.

抽象的哮喘是气道的一种慢性炎症性疾病，T细胞表现出偏见的Th2/Th17 分化和多动性表型。后者与持续的细胞内信号传导有关。信号传导过程通常是由于负稳态调节而导致的。有一个知识差距我们对诱导持续信号传导的机制的理解。我们建议描述哮喘中T细胞中持续信号传导的诱导。我们报道了信号分子发芽 2（Spry 2）在建立ERK1/2的自我维持的信号传导机制中起着至关重要的作用。解决进一步，我们生成了CD4靶向SPRY 2基因敲除小鼠。 Spry2 - / - T细胞增加了CBL-B，并且 NEDD4减少。上述泛素连接酶在拮抗的调节TCR泛素化，内吞作用，退化，从而控制TCR信号输出。由于这些受体近端异常SPRY2 - / - T细胞的信号传导和增殖受损。这些障碍变得更加 CD28参与后发音。 SPRY2 - / - T细胞受损TH2/TH17分化。他们是无法在小鼠哮喘模型中安装气道炎症，过度反应性和重塑。基于根据这些初步结果，我们假设Spry 2通过形成A来扩展并延长T细胞信号传导三方调节网络，其中Spry 2和NEDD4拮抗CBL-B的信号终止作用。 spry2-- 驱动的放大和信号传导对共同刺激，TH2/TH17分化和哮喘的发展。在特定目标1下，我们将研究Spry 2在产生持续的作用 T细胞中的信号传导。我们将定义CD3-，尤其是CD28诱导的信号通路的范围由Spry 2调节。我们将检查CBL-B和NEDD4对SPRY2敲除的贡献表型。具体目标2将研究Spry 2在体外对Th2和Th17细胞分化的重要性体内spry2 - / - 小鼠。我们将描述Spry 2调节Th2/Th17的信号传导机制分化。在特定目标3下，我们将描述Spry 2在诱导和维持炎症中的作用在慢性哮喘的小鼠模型中。我们将检查CBL-B淘汰赛是否逆转SPRY2淘汰赛表型。在特定目标4下，我们将研究哮喘患者的CD4 T细胞中Spry 2的表达并检查其对哮喘中多动性T细胞表型和偏差分化的贡献。这些研究很重要，因为它们已经发现了迄今涉及SPRY2的未知调节网络， CBL-B和NEDD4，控制TH2/TH17哮喘的分化和发育。