SALIVARY MUCOUS CELL GENE EXPRESSION

描述：需要阐明控制唾液外分泌细胞分化的机制，以开发基于细胞的疗法来治疗头颈部放疗后的患者或患有自身免疫性疾病的患者。我们正在研究NFS/N-SLD小鼠，以阐明唾液粘液细胞分化的因素。在初步研究中，我们发现了一种新的小鼠基因(MSLG MUC)，编码在小鼠舌下腺中表达的无粘蛋白，并有生物信息学证据表明存在同线人类同源物。由于这些无粘蛋白可能代表黏液细胞特有的基因产物，它们是研究黏液细胞分化和基因表达的极佳焦点。因此，我们将：1)描述mSLG、MUC、apomucin基因的基因组组织及其组织和细胞特异性表达。我们还将检验一种假设，即与mSLG MUC同源的假定的人类基因在人类唾液腺中表达，如果是这样的话，描述其基因组组织。我们将SLD突变基因定位于一个基因缺失的临界区(=15号染色体上的1.2兆碱基)，其中包括mSLG MUC。我们将：2)确定含有SLD突变的基因，并调查与SLD表型相关的病变。SLD小鼠粘液细胞表达的增加似乎与腺体稳定的无粘蛋白转录物和粘蛋白糖蛋白水平有关。我们的综合数据表明SLD的表型与无蛋白粘蛋白的表达有关。有趣的是，最近发现神经内分泌细胞的主要分泌产物，嗜铬粒素A，在分泌颗粒的生物发生和调节外分泌中起着限速步骤的作用。通过类比，我们推测舌下无粘蛋白具有促进粘液细胞终末分化的作用。因此，我们将：3)确定[sl]调节无粘蛋白转录本稳定水平的机制，并验证mSLG、MUC无粘蛋白促进粘液细胞表型终末分化的假设。从这些联合研究中，我们确定了一个新的基因，mSLG MUC，它可能代表了唯一已知的在唾液粘液细胞中选择性表达的基因。我们还将评估Mslg MUC在黏液细胞终末分化中的作用，并确定其与SLD突变的关系。此外，一种表达唾液无粘蛋白的新的人类基因的表达将得到验证，如果表达，将成为未来研究的重点，以确定其表达的调节机制。

DESCRIPTION: Elucidation of mechanisms controlling differentiation of salivary exocrine cells is required for development of cell-based therapeutics to treat patients after head/neck radiation or with autoimmune diseases. We are studying NFS/N-sld mice to elucidate factors in the differentiation of salivary mucous cells. In preliminary studies, we've identified a novel mouse gene (mSLG MUC) encoding the apomucin expressed in murine sublingual glands and have bioinformatic evidence for a syntenic human homologue. As these apomucins may represent gene products specific for mucous cells they are excellent focal points to study mucous cell differentiation and gene expression. We thus will: 1) Delineate the genomic organization of the mSLG MUC apomucin gene and its tissue and cell specific expression. We will also test the hypothesis that a putative human gene syntenic to mSLG MUC is expressed in human salivary mucous glands, and if so, delineate its genomic organization. We genetically mapped the sld mutation to a gene-poor critical region (=1.2 megabases on chromosome 15) that includes mSLG MUC. We will: 2) Determine the gene harboring the sld mutation and investigate the associated lesion responsible for the sld phenotype. The increase in mucous cell expression in sld-mice appears related to both glandular steady-state levels of apomucin transcripts and mucin glycoproteins. Our combined data indicate the sld phenotype is linked to expression of the apomucin. Interestingly, it has recently been determined that the major secretion product of neuroendocrine cells, chromogranin A, functions as a rate-limiting step in the biogenesis of secretory granules and regulated exocrine secretion. By analogy, we posit the sublingual apomucin functions to promote terminal differentiation of mucous cells. We will therefore: 3) Determine mechanism[sl by which steady-state levels of apomucin transcripts are regulated and also test the hypothesis that the mSLG MUC apomucin functions to promote the terminal differentiation of the mucous cell phenotype. From these combined studies, we characterize a novel gene, mSLG MUC, that likely represents the only known gene to be expressed selectively in salivary mucous cells. We also will evaluate the role of Mslg MUC in the terminal differentiation of mucous cells and determine its relationship to the sld mutation. Moreover, expression of a novel human gene expressing a salivary apomucin will be verified, and if expressed, would be the focus of future studies to determine mechanisms regulating its expression.