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

描述（由申请人提供）：最近的工作涉及到几个已知参与控制细胞生长、分化和凋亡的信号分子，这些信号分子与Th2分化和功能的调节有关。然而，关于这些不同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未得到解答。这一建议是基于我们之前对非典型PKCs和p62信号通路参与Th2分化的研究。Th2极化系统不仅从哮喘和其他过敏性疾病的角度来看很重要，而且也是细胞分化的一个非常有趣的范例，其中不同信号通路之间的相互作用，包括NF-？B和Jak1/Stat6级联，以确保极化途径的效率和选择性。Th2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，全球哮喘患病率呈上升趋势，美国约有1500万人患有该病，其中500万为儿童。这里提出的研究的长期目标是揭示涉及Th2分化的信号级联反应，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验证p62和aPKCs在这些过程中起重要作用的假设。具体来说，我们将确定p62在Th2功能中的作用和作用机制，重点关注p62调节NF-？B在Th2分化过程中的激活，以及PKC的潜在作用？在这个级联中。这将使用带有“floxed”PKC的鼠标来解决？在使用p62和PKC的研究中？-缺陷小鼠和细胞。此外，我们将开展研究，从机制层面了解PKC如何？，还有PKC ?/？在IL-4/Stat6级联中调控Jak1。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、毒性更小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，涉及气道炎症。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，全世界哮喘患病率呈上升趋势。哮喘和其他过敏性疾病的病理与CD4+ Th2细胞的异常活化有关。最近的研究表明，在Th2分化和功能的调控中，一些已知的信号分子参与了细胞生长、分化和凋亡的控制。然而，关于这些不同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未得到解答。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，也将有助于开发新的、毒性更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.