The p62/atypical PKC signaling complex in Th2 differentiation and asthma

描述(由申请人提供)：最近的工作涉及几个已知参与控制细胞生长、分化和凋亡的信号分子，涉及Th2分化和功能的调节。然而，关于这些不同信号通路之间的相互作用以及它们在体内的相对重要性的关键问题仍然没有答案。这一建议是基于我们之前对参与Th2分化的非典型PKCs和p62信号通路的研究。Th2极化系统不仅从哮喘和其他过敏性疾病的角度来看是重要的，而且也是一个非常有趣的细胞分化范例，在这个范例中，不同信号通路之间的串扰被启动，包括NF-β和JAK1/STAT6级联，以确保极化通路的效率和选择性。Th2分化异常会导致哮喘，这是一种涉及呼吸道炎症的慢性肺部疾病。流行病学研究表明，自1980年以来，哮喘的患病率在全球范围内有所上升，美国约有1500万人患有这种疾病，其中500万是儿童。这些研究的长期目标是解开Th2分化所涉及的信号级联反应，这在控制过敏性疾病，特别是哮喘方面将是至关重要的。这项提案的总体目标是检验这样一种假设，即P62和APKC是这些进程中的关键角色。具体地说，我们将确定p62在Th2功能中的作用和作用机制，重点讨论p62在Th2分化过程中调节核因子-βB激活的持续阶段的途径，以及PKC？/？在这一级联反应中的潜在作用。这将通过使用带有PKC？/？基因的小鼠来解决，并在使用p62和PKC？缺陷小鼠和细胞的研究中解决。此外，我们将开展研究，以在机械水平上了解PKC？，以及潜在的PKC？/？调节IL-4/Stat6级联反应中的JAK1。这些体外和体外研究的所有结果将在体内系统中得到验证，我们将在过敏性呼吸道炎症的小鼠模型中评估这些分子与哮喘的相关性。这项研究将增加我们对Th2分化和哮喘调节的不同机制的理解，也可能有助于开发新的、毒性较低的过敏性肺部炎症治疗方法。公共卫生相关声明：哮喘是一种慢性肺部疾病，涉及呼吸道炎症。在美国，它影响了大约1500万人，其中500万是儿童，被认为是儿童住院和缺课的最常见原因。流行病学研究表明，自1980年以来，哮喘的患病率在全球范围内呈上升趋势。哮喘和其他过敏性疾病的病理与CD4+Th2细胞的异常激活有关。最近的工作涉及几个已知参与控制细胞生长、分化和凋亡的信号分子，它们调控Th2的分化和功能。然而，关于这些不同信号通路之间的相互作用以及它们在体内的相对重要性的关键问题仍然没有答案。这项研究将加深我们对Th2分化和哮喘调节的不同机制的理解，也将有助于开发新的、毒性较低的过敏性肺部炎症治疗方法。

DESCRIPTION (provided by applicant): Recent work has implicated several signaling molecules that are known to be involved in the control of cell growth, differentiation, and apoptosis related to the regulation of Th2 differentiation and function. However, key questions concerning the interactions among these different signaling pathways and their relative importance in vivo remain unanswered. This proposal is based on our previous studies of atypical PKCs and p62 signaling pathways involved in Th2 differentiation. The Th2 polarization system is not only important from the point of view of asthma and other allergic diseases, but is also a very interesting paradigm of cell differentiation in which the crosstalk between different signaling pathways, including NF-?B and the Jak1/Stat6 cascade, are set in motion to ensure the efficiency and selectivity of the polarization pathways. Aberrations in Th2 differentiation lead to asthma, a chronic lung condition involving inflammation of the airways. Epidemiological studies demonstrate that there has been a worldwide increase in the prevalence of asthma since 1980, and that this disease affects about 15 million people in the US, of which 5 million are children. The long-term goal of the studies proposed here is to unravel the signaling cascades involved in Th2 differentiation, which will be critical in the control of allergic diseases, especially asthma. The overall objective of this proposal is to test the hypothesis that p62 and the aPKCs are essential players in these processes. Specifically, we will determine the role and mechanism of action of p62 in Th2 function, focusing on the pathways whereby p62 regulates the sustained phase of NF-?B activation during Th2 differentiation, as well as the potential role of PKC ?/??in this cascade. This will be addressed using mice with a "floxed" PKC ?/??gene, and in studies using p62- and PKC?-deficient mice and cells. Additionally, we will carry out studies to understand at a mechanistic level how PKC?, and potentially also PKC ?/? regulate Jak1 in the IL-4/Stat6 cascade. All the results from these ex vivo and in vitro studies will be validated in in vivo systems where we will assess the relevance of these molecules to asthma in a mouse model of allergic airway inflammation. This study will increase our understanding of the different mechanisms involved in the regulation of Th2 differentiation and asthma, and could also contribute to the development of novel and less toxic therapies for allergic pulmonary inflammation. Public Health Relevance Statement: Asthma is a chronic lung condition involving inflammation of the airways. It affects about 15 million people in the US, of which 5 million are children, and is considered to be the most common reason for childhood hospitalizations and school absenteeism. Epidemiological studies demonstrate that since 1980 there has been a worldwide increase in the prevalence of asthma. The pathology of asthma and other allergic diseases is associated with aberrant activation of CD4+ Th2 cells. Recent work has implicated several signaling molecules that are known to be involved in the control of cell growth, differentiation, and apoptosis in the regulation of Th2 differentiation and function. However, key questions concerning the interactions among these different signaling pathways and their relative importance in vivo remain unanswered. This study will increase our understanding of the different mechanisms involved in the regulation of Th2 differentiation and asthma, and would also contribute to the development of novel and less toxic therapies for allergic pulmonary inflammation.