Functional Characterization of CXCL14, CXCL17, and CCL28; three mucosal chemokine

描述(申请人提供)：粘膜免疫包括许多分子实体，其中许多仍然知之甚少。我们利用基因芯片分析鉴定了三种趋化因子(CXCL14、CXCL17和CCL28)，它们在人的粘膜组织中表现出非常高的表达。在已知的48种人类配体中，只有这三种趋化因子与粘膜组织有如此密切的联系。这些趋化因子可能代表了一些最丰富的蛋白质，例如，在人类唾液中，但我们对它们知之甚少。此外，它们在粘膜免疫中的作用几乎还没有被探索过。因此，我们的目标是研究这些“粘膜”趋化因子。在特定的目标1中，我们将通过免疫组织化学和/或原位杂交，在不同的粘膜组织(口腔、支气管、气管、食道、肠道和女性生殖道)中定位产生这些趋化因子的细胞。这些结果将指向未来旨在更详细地评估这些趋化因子在粘膜免疫中的作用的实验。在特定的目标2中，我们将检验这些趋化因子具有杀微生物活性的假设。我们将检测几种微生物，包括革兰氏(+)、革兰氏(-)、白色念珠菌和沙眼衣原体。如果得到证实，这一结果将表明这些趋化因子可能是维持人体空洞粘膜与这些部位存在的正常或致病菌群之间的平衡的主要因素。例如，这些趋化因子可能在牙周病或阴道念珠菌病等疾病中发挥主要作用。最后，我们观察到其中一种趋化因子CXCL14在味蕾中特异表达，但在舌上皮中不表达。我们将使用味蕾细胞的各种生物标记物(那些调节甜味、苦味、鲜味和酸味的细胞以及前体味觉细胞)来分析CXCL14基因敲除小鼠的味蕾。这些实验将表明CXCL14-/-小鼠的味蕾是否表现出任何变化，并可能指出CXCL14在味蕾发育中的作用。综上所述，这些实验应该会让我们对这些趋化因子在粘膜组织中的功能有一个新的理解。本项目旨在研究三种趋化因子(CXCL14、CXCL17、CCL28)在粘膜组织中的高表达，包括在各种体腔(口腔、阴道等)中的表达。它将探索这些趋化因子的几个潜在功能，包括杀菌活性以及CXCL14在味蕾发育中的潜在作用。

DESCRIPTION (provided by applicant): Mucosal Immunity includes many molecular entities, many of which remain poorly understood. We have used gene array analyses to identify three chemokines (CXCL14, CXCL17 and CCL28) that exhibit very high expression in human mucosal tissues. Only these three chemokines (out of 48 known human ligands) exhibit this close association with mucosal tissues. These chemokines likely represent some of the most abundant proteins present, for example, in human saliva, yet we know very little about them. Furthermore, their role in mucosal immunity is virtually unexplored. We therefore aim to study these 'mucosal' chemokines. In Specific aim 1, we will map the cells that produce these chemokines in the various mucosal tissues (oral cavity, bronchus, trachea, esophagus, gut and the female reproductive tract) by immunohistochemistry and/or in situ hybridization. These results will point to future experiments aimed at evaluating in greater detail the role of these chemokines in mucosal immunity. In Specific aim 2, we will test the hypothesis that these chemokines have microbicidal activity. We will test several microorganisms, including gram (+), gram (-), Candida albicans and Chlamydia trachomatis. If confirmed, this result would indicate that these chemokines may be major players in maintaining the balance between the mucosa of human body cavities and normal or pathogenic flora present in these sites. For example, these chemokines may play major roles in diseases such as periodontal disease, or vaginal candidiasis. Finally, we have observed that one of these chemokines, CXCL14, is specifically expressed in taste buds but not in lingual epithelium. We will analyze the taste buds of CXCL14 knockout mice using various biomarkers of taste bud cells (those that mediate sweet, bitter, umami and sour taste perception as well as precursor taste cells). These experiments will indicate whether the taste buds of CXCL14-/- mice exhibit any alterations and may point to a role for CXCL14 in taste bud development. Taken together, these experiments should provide us with a new understanding of the functions of these chemokines in mucosal tissues. This project aims to characterize three chemokines (CXCL14, CXCL17, CCL28) that are highly expressed in mucosal tissues including those in various human body cavities (oral cavity, vagina, etc). It will explore several potential functions of these chemokines including microbicidal activity as well as a potential role of CXCL14 in taste bud development.