Defining mechanisms for how Ndfip1 regulates T cell-mediated allergic responses

描述（由申请人提供）：特应性疾病，如哮喘、特应性皮炎（AD）和炎症性肠病（IBD），是最常见的儿童慢性疾病之一，也是儿童住院治疗的常见原因。这些疾病的特点是抗原暴露部位的炎症，即肺、皮肤和胃肠道。炎症的特征是血清IgE升高，嗜酸性粒细胞增多，T细胞产生高水平的辅助性T型2 （Th2）型细胞因子。虽然特应性疾病有很强的遗传成分，但遗传因素在很大程度上是未知的。我们的初步数据表明，nedd4家族相互作用蛋白-1 （Ndfipl）调节小鼠的特应性炎症，也可能在人类的特应性疾病中发挥作用。例如，我们已经证明缺乏Ndfipl的小鼠在皮肤、肠道和肺部会发生严重的炎症性疾病，再现了人类AD、IBD和哮喘的表型。此外，我们在编码Ndfipl的基因座中发现了在哮喘、AD和IBD患者中更常见的多态性。为了理解为什么Ndfipl-/- T细胞具有高反应性，我们将研究重点放在了调节性T （Treg）细胞反应上。treg是一种特殊的T细胞亚群，可以抑制常规T细胞的反应。因此，treg在维持对自身抗原和环境过敏原的耐受性方面起着关键作用。本文提出的研究将验证Ndfipl在抗原暴露位点调控Treg发育和/或功能的假设。为实现这一目标，我们将决定；1)自然产生的胸腺源Treg （ntreg）在Ndfipl缺陷小鼠中是否存在缺陷，2)缺乏Ndfipl的T细胞在转化为Treg（诱导Treg）时是否存在缺陷，3)Ndfipl-/-小鼠中产生的炎症细胞因子是否会阻止过敏原暴露部位的Treg重新转化。这些研究将帮助我们定义由Ndfipl调控的细胞类型和途径，并促进我们对Ndfipl如何调控特应性疾病的理解。我们的长期目标是靶向Ndfipl通路治疗特应性疾病患者。这里提出的研究将有助于我们实现这一目标。通俗地说，我们提出的研究将帮助我们了解调节小鼠和人类特应性疾病的蛋白质Ndfipl的功能。具体来说，我们将描述Ndfipl在称为调节性T细胞的T细胞亚群中的作用，因为它们具有“调节”免疫功能的能力而被恰当地命名。这些研究旨在了解调节性T细胞如何在缺乏Ndfipl的小鼠中促进特应性疾病，并对哮喘、特应性皮炎和炎症性疾病的发病机制和治疗具有广泛的意义。

DESCRIPTION (provided by applicant): Atopic diseases, such as asthma, atopic dermatitis (AD), and inflammatory bowel disease (IBD), are among the most common chronic childhood illnesses and a frequent cause of pediatric hospitalization. These diseases are characterized by inflammation at sites of antigen exposure, namely the lung, skin and gastrointestinal (Gl) tract. The inflammation is characterized by the presence of elevated serum IgE, eosinophilia, and T cells that produce high levels of T helper type 2 (Th2) type cytokines. While there is a strong genetic component to atopic disease, contributing genetic factors are largely unknown. Our preliminary data indicate that Nedd4-family interacting protein-1 (Ndfipl) regulates atopic inflammation in mice, and may also play a role in atopic diseases in man. For example, we have shown that mice lacking Ndfipl develop a severe inflammatory disease in the skin, gut, and lung that recapitulates the phenotype of AD, IBD, and asthma in humans. Furthermore, we have identified polymorphisms that are more common in patients with asthma, AD, and IBD within the locus that encodes Ndfipl. In an attempt to understand why Ndfipl-/- T cells are hyperresponsive, we have focused our efforts on regulatory T (Treg) cell responses. Tregs are a specialized subset of T cells that suppress the response of conventional T cells. Thus, Tregs play a key role in the maintenance of tolerance to self-antigens as well as environmental allergens. The studies proposed here will test the hypothesis that Ndfipl regulates Treg development and/or function at the sites of antigen exposure. To accomplish this we will determine; 1) Whether naturally-occurring thymus- derived Tregs (nTregs) are defective in Ndfipl deficient mice, 2) Whether T cells lacking Ndfipl are defective at converting into Tregs (induced Tregs), 3) Whether the inflammatory cytokines produced in Ndfipl-/- mice prevent de novo Treg conversion at sites of allergen exposure. These studies will help us to define cell types and pathways regulated by Ndfipl and advance our understanding of how Ndfipl regulates atopic disease. Our long-term goal is to therapeutically target Ndfipl pathways to treat patients with atopic diseases. The studies proposed here will help us towards this goal. In lay terms, our proposed studies will help us to understand the function of a protein, Ndfipl, that regulates atopic disease in mice and man. Specifically, we will characterize the role of Ndfipl in a subset of T cells called regulatory T cells, aptly named because of their capacity to "regulate" immune function. These studies are aimed at understanding how regulatory T cells contribute to atopic disease in mice lacking Ndfipl and have broad implications for the pathogenesis and treatment of asthma, atopic dermatitis, and inflammatory disease.