Oral Mucins as a Diagnostic Indicator and Therapeutic Treatment for Xerostomia

性状（由申请方提供）：粘蛋白是覆盖暴露于环境的身体部位（包括气道、消化道、泌尿生殖系统和口腔）的粘液的主要成分。粘蛋白通常是由连接到多个复杂寡糖链的蛋白质核心组成的大分子。粘蛋白执行许多保护功能，包括组织表面的水合和润滑以及与病原体的相互作用，无论是单独的还是作为与唾液或粘液的其他组成蛋白的大复合物的一部分。在唾液中，来自唾液腺的分泌物贡献至少两种粘蛋白。另外两种粘蛋白已经定位于口腔组织（如脸颊和上颚）的上皮细胞。在人类唾液腺RNA的初步实验中，我们在口腔组织中发现了多个额外的粘蛋白转录本。考虑到多种粘蛋白在口腔中的表达及其在水合和润滑中的作用，我们假设患有口腔疾病（如干燥综合征和灼口综合征）的患者的口腔干燥（口干症）的主观主诉与口腔上皮和/或唾液腺的一种或多种粘蛋白表达的改变相关。粘蛋白表达的变化可以解释为什么许多患者抱怨口干（口腔干燥），但他们产生正常的唾液流动。为了初步验证我们的假设，并为随后的RO 1应用提供初步数据，我们将比较健康人对照组和三个单独的口干症患者组（每组10名受试者）之间唾液和口腔上皮细胞样本中粘蛋白基因的表达。这些患者组包括患有灼口综合征的患者和两组患有干燥综合征的患者;唾液分泌不足的患者和流量在正常范围内的患者。我们的试点研究有两个具体目标。目的一是发展以抗体为基础的粘蛋白表达的检测方法以及口腔上皮细胞的采集技术。目的二是确定对照组和每个患者组之间在全唾液内的粘蛋白和/或与源自口腔的两个不同区域的口腔上皮细胞相关的粘蛋白的表达方面的差异。这项初步研究的结果是必要的，以证明资助后续的更大的研究，重点是那些粘蛋白，显示出统计学差异或变化的表达之间的控制和一个或多个患者组的趋势。鉴定与主观口腔干燥相关的一种或多种粘蛋白的改变的表达可最终导致：1）在口腔疾病的早期阶段以及在随后的疾病进展期间，当唾液流变得受损时，改善对患者的诊断; 2）通过向口腔冲洗液中添加适当的粘蛋白或粘蛋白替代物来缓解口腔干燥的生化疗法; 3）基因疗法以适当的口服靶点来抵消粘蛋白表达的变化;或4）通过描绘控制粘蛋白基因表达的因素来进一步了解导致疾病起始或进展的生物学机制。 公共卫生相关性： 在许多情况下，口腔疾病与口干的感觉（有或没有唾液产生的显著减少）和伴随的生活质量下降有关。与口腔干燥的主观主诉相关的一种或多种粘蛋白的改变的表达的鉴定可最终导致：1）在口腔疾病的早期阶段以及在唾液流变得受损时的随后疾病进展期间改善患者的诊断; 2）缓解口腔干燥的疗法，通过向口腔冲洗液中添加适当的粘蛋白、粘蛋白组分或粘蛋白替代物;或3）基因疗法或药物以抵消粘蛋白表达的变化。

DESCRIPTION (provided by applicant): Mucins are a primary component of mucus covering those parts of the body exposed to the environment, including the airways, digestive tract, urogenital system, and the oral cavity. Mucins are generally large molecules composed of a protein core linked to multiple complex oligosaccharide chains. Mucins perform many protective functions, including hydration and lubrication of tissue surfaces as well as interaction with pathogens, either alone or as part of large complexes with other constituent proteins of saliva or mucus. In saliva, secretions from salivary glands contribute at least two mucins. Two other mucins have been localized to epithelial cells lining oral tissues such as the cheeks and palate. In preliminary experiments with human salivary gland RNA, we discovered multiple additional mucin transcripts in oral tissues. Given the expression of multiple mucins in the oral cavity and their role in hydration and lubrication, we hypothesize that the subjective complaint of oral dryness (xerostomia) by patients suffering from oral diseases, such as Sjvgren's syndrome and Burning Mouth Syndrome, is associated with an alteration in expression of one or more mucins by the oral epithelium and/or salivary glands. A change in mucin expression may explain why many patients complain of a dry mouth (xerostomia), yet they produce a normal flow of saliva fluid. To initially test our hypothesis and provide preliminary data for a subsequent RO1 application, we will compare mucin gene expression in samples of saliva and oral epithelial cells between healthy human controls and three separate patient groups that present with xerostomia (10 subjects per group). These patient groups include those with Burning Mouth Syndrome and two groups of patients with Sjvgren's syndrome; those that are hyposalivary and those with flow in the normal range. Our pilot study has two specific aims. Aim one is to develop antibody-based assays of mucin expression as well as techniques to collect oral epithelial cells. Aim two is to determine differences between the control group and each patient group in the expression of mucins within whole saliva and/or of mucins associated with oral epithelial cells derived from two different regions of the oral cavity. Results from this pilot study are necessary to justify funding for a subsequent larger study focused on those mucins that display either a statistical difference or a trend for altered expression between the control and one or more patient group(s). Identification of the altered expression of one or more mucins in association with subjective oral dryness may ultimately lead to: 1) Improved diagnostics of patients in the early stages of oral disease as well as during subsequent disease progression, when salivary flow becomes compromised; 2) Biochemical therapies to relieve oral dryness, either through addition of appropriate mucin(s) or mucin surrogates to oral rinses; 3) Gene therapies to appropriate oral targets to counteract changes in mucin expression; or 4) Further insights into biological mechanisms that lead to disease initiation or progression by delineation of factors that control mucin gene expression. PUBLIC HEALTH RELEVANCE: Diseases of the oral cavity in many instances are associated with the perception of a dry mouth (either with or without a marked decrease in saliva production) and a concomitant decrease in the quality of life. Identification of the altered expression of one or more mucins in association with the subjective complaint of oral dryness may ultimately lead to: 1) Improved diagnostics of patients during the early stages of oral disease, as well as during subsequent disease progression when salivary flow becomes compromised; 2) Therapies to relieve oral dryness, either through addition of appropriate mucin(s), mucin components, or mucin surrogates to oral rinses; or 3) Gene therapies or pharmaceuticals to counteract changes in the expression of mucins.