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

描述（由申请人提供）：最近的工作涉及已知参与与调节Th 2分化和功能相关的细胞生长、分化和凋亡的控制的几种信号分子。然而，关于这些不同的信号通路之间的相互作用及其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以前的非典型PKCs和p62信号通路参与Th 2分化的研究。Th 2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，但也是一个非常有趣的细胞分化的范例，其中不同的信号通路，包括NF-？B和Jak 1/Stat 6级联被启动以确保极化路径的效率和选择性。Th 2分化的异常导致哮喘，这是一种涉及气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增加，并且这种疾病影响美国约1500万人，其中500万是儿童。本文提出的研究的长期目标是解开参与Th 2分化的信号级联，这将是控制过敏性疾病，特别是哮喘的关键。本提案的总体目标是检验p62和aPKC在这些过程中是必不可少的参与者的假设。具体而言，我们将确定的作用和机制的行动p62在Th 2功能，重点是p62调节NF-？Th 2分化过程中B活化，以及PKC？/？？在这个瀑布。这将解决使用小鼠与“floxed”蛋白激酶C？/？？基因，并在研究中使用p62-和PKC？-缺陷小鼠和细胞。此外，我们将进行研究，以了解在机制水平如何PKC？，也可能是PKC？/？调节IL-4/Stat 6级联中的Jak 1。这些离体和体外研究的所有结果将在体内系统中得到验证，我们将在过敏性气道炎症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调节Th 2分化和哮喘的不同机制的理解，也可能有助于开发新的毒性较小的过敏性肺部炎症治疗方法。公共卫生相关性声明：哮喘是一种涉及气道炎症的慢性肺部疾病。它影响了美国约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，哮喘的流行率在全球范围内有所增加。哮喘和其他过敏性疾病的病理学与CD 4 + Th 2细胞的异常活化有关。最近的工作已经涉及已知参与控制细胞生长、分化和凋亡的几种信号分子，其参与调节Th 2分化和功能。然而，关于这些不同的信号通路之间的相互作用及其在体内的相对重要性的关键问题仍然没有答案。这项研究将增加我们对Th 2分化和哮喘调节中所涉及的不同机制的理解，也将有助于开发新型和毒性较小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.