Mouse Asthma

小鼠哮喘模型核心(Science Core C)将协调和执行项目中的实验 2、3和4，涉及小鼠哮喘模型。在项目4中，领导者斯皮格尔博士已经开发出 神经鞘氨醇-1-激酶的特异性抑制剂，并将在吸入模型中使用这些药物直接使它们 肺部。这在很大程度上避免了全身毒性，并直接针对受影响的器官。这个概念是 测试的是抑制肺肥大细胞是否足以抑制哮喘模型。此外， 项目主任将使用siRNA在体内阻断肺内鞘氨醇激酶的合成，以便 确定这是否会抑制哮喘的发展。在项目2中，康拉德博士已经证明了 CD23的过度表达抑制了IgE的产生和嗜酸性粒细胞向肺的募集。实验将会 以确定IgE是否为嗜酸性粒细胞募集所必需。此外，CD23 Sheddase已被鉴定为Adam 10，siRNA敲除实验将在 与Spiegel博士合作确定是否通过siRNA或特定的基因在肺中阻断ADAM10 抑制剂会影响哮喘的发展和症状。在项目3中，瑞安博士正在检查 LYN基因敲除动物的过敏表型，目的是测定LYN在 肥大细胞。LYN“‘”小鼠已知会患上严重的Th2疾病，包括IgE升高和 嗜酸性粒细胞反应。毫不奇怪，这些活动会导致严重的哮喘表型。在……里面 与康拉德博士合作，LYN“‘”动物将与CD23转基因杂交，看看Th2是否 疾病是被调节的。此外，ADAM10抑制剂的活性可以通过siRNA或化学物质来实现 直接引入肺部的抑制剂方法学将测试其调节LYN的能力。 严重的Th2疾病模式。在所有这些研究中，核心将提供专业知识来执行 并分析小鼠哮喘模型的数据。这些措施包括对小鼠进行30天的维护 BAL液体收集和最终牺牲所需的敏化、气溶胶挑战和终极牺牲时间 肺组织学和RNA分析的准备。

The mouse asthma model core (scientific core C) will coordinate and perform the experiments in projects 2, 3 and 4 that involve the mouse asthma model. In Project 4, the Leader, Dr. Spiegel, has developed specific inhibitors for sphingosine-1-kinase and will use these in an inhalent model to get them directly to the lung. This largely avoids systemic toxicity and targets the affected organ directly. The concept being tested is whether inhibition of lung mast cells is sufficient to inhibit the asthma model. In addition, the program director will use siRNA to block, in vivo, in lung the synthesis of sphingosine kinase in order to determine whether this will inhibit asthma development. In Project 2, Dr. Conrad has demonstrated that overexperssion of CD23 inhibits IgE production and eosinophil recruitment to the lung. Experiments will be performed to determine if IgE is necessary for the eosinophil recruitment. In addition, the CD23 sheddase has been identified as ADAM 10 and siRNA knock-down experiments will be performed in collaboration with Dr. Spiegel to determine if blockade of ADAM10 in the lung, either by siRNA or specific inhibitors influences asthma development and symptoms. In Project #3, Dr. Ryan is examining the allergic phenotype of lyn knockout animals with the objective of determining the activities of lyn in the mast cell. The lyn"'" mice are known to develop severe Th2 disease including increased IgE and eosinophil responses. These activities, not surprisingly, lead to a severe asthma phenotype. In collaboration with Dr, Conrad, the lyn"'" animals will be crossed to CD23 transgenics to see if the Th2 disease is modulated. In addition, the activities of ADAM10 inhibitors either via a siRNA or chemical inhibitor methodology, introduced directly into the lung, will be tested for capacity to modulate the lyn"'" severe Th2 disease modality. In all of these studies, the core will provide the expertise to both perform and analyze data from the mouse asthma model. These include maintenance of mice for the 30 day period required for sensitization, aerosol challenge and ultimate sacrifice with BAL fluid collection and lung preparation for histology and RNA analysis.