Oral Mucins as a Diagnostic Indicator and Therapeutic Treatment for Xerostomia

描述(申请人提供)：粘蛋白是覆盖身体暴露在环境中的部分的粘液的主要成分，包括呼吸道、消化道、泌尿生殖系统和口腔。粘蛋白通常是由连接到多个复杂的寡糖链的蛋白质核心组成的大分子。粘蛋白具有许多保护功能，包括组织表面的水化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型复合体的一部分。在唾液中，唾液腺的分泌物至少贡献两种粘蛋白。另外两种粘蛋白已经定位于口腔组织衬里的上皮细胞，如脸颊和腭部。在对人类唾液腺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。鉴于多种粘蛋白在口腔中的表达及其在水化和润滑中的作用，我们假设患有口腔疾病(如干燥综合征和灼口综合征)的患者主观主诉口腔干燥(口干)与口腔上皮和/或唾液腺表达一种或多种粘蛋白有关。粘蛋白表达的变化可能解释了为什么许多患者抱怨口干(口干症)，但他们产生正常的唾液流动。为了初步验证我们的假设，并为后续的RO1应用提供初步数据，我们将比较健康人类对照组和三个单独的口干症患者组(每组10名受试者)唾液和口腔上皮细胞样本中的粘蛋白基因表达。这些患者组包括灼口综合征患者和两组干燥综合征患者；输卵管功能低下和血流正常的患者。我们的初步研究有两个具体目标。目的之一是开发基于抗体的粘蛋白表达分析方法以及收集口腔上皮细胞的技术。第二个目的是确定对照组和每个患者组在全唾液和/或来自口腔两个不同区域的口腔上皮细胞相关粘蛋白的表达上的差异。这项先导性研究的结果对于为随后的更大规模的研究提供资金是必要的，该研究的重点是那些在对照组和一个或多个患者组(S)之间显示统计差异或表达变化趋势的粘蛋白。发现一个或多个粘蛋白的表达变化与主观口腔干燥有关，最终可能有助于：1)在口腔疾病的早期阶段以及随后的疾病发展过程中，当唾液流量受到影响时，改善患者的诊断；2)通过在口腔漱口水中添加适当的粘蛋白(S)或替代粘蛋白来缓解口腔干燥；3)针对适当的口腔靶点进行基因治疗，以抵消粘蛋白表达的变化；或4)通过描述控制粘蛋白基因表达的因素，进一步深入了解导致疾病发生或进展的生物机制。 与公共卫生相关：在许多情况下，口腔疾病与口腔干燥(有或没有唾液分泌明显减少)的感觉以及随之而来的生活质量下降有关。发现一种或多种粘蛋白的表达变化与口腔干燥的主观主诉相关，最终可能导致：1)在口腔疾病的早期阶段，以及在随后的唾液流动受损的疾病进展期间，改善患者的诊断；2)通过在口腔漱口水中添加适当的粘蛋白(S)、粘蛋白成分或粘蛋白替代品来缓解口腔干燥的治疗；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.