SALIVARY MUCOUS CELL GENE EXPRESSION

描述：阐明控制唾液外分泌细胞分化的机制是开发以细胞为基础的治疗方法来治疗头颈部放疗后或自身免疫性疾病患者的必要条件。我们正在研究NFS/N-sld小鼠，以阐明唾液黏液细胞分化的因素。在初步研究中，我们发现了一种新的小鼠基因（mSLG MUC）编码小鼠舌下腺中表达的apomucin，并有生物信息学证据表明其与人类同源。由于这些apomucins可能代表了黏液细胞特异性的基因产物，它们是研究黏液细胞分化和基因表达的极好焦点。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。我们还将测试一个假定的与mSLG MUC同步的人类基因在人类唾液黏液腺中表达的假设，如果是这样，描述其基因组组织。我们将sld突变基因定位到包括mSLG MUC在内的基因贫乏关键区域（15号染色体上=1.2兆碱基）。我们将：2)确定携带sld突变的基因，并研究导致sld表型的相关病变。sld小鼠黏液细胞表达的增加似乎与腺稳态水平的粘蛋白转录本和粘蛋白糖蛋白有关。我们的综合数据表明，sld表型与apomucin的表达有关。有趣的是，最近已经确定，神经内分泌细胞的主要分泌产物，嗜铬粒蛋白A，在分泌颗粒的生物发生和调节外分泌中起限速作用。以此类推，我们假设舌下apomucin具有促进黏液细胞终末分化的功能。因此，我们将：3)确定apomucin稳态水平被调控的机制[sl]，并验证mSLG MUC apomucin促进黏液细胞表型终末分化的假设。从这些综合研究中，我们描述了一个新的基因，mSLG MUC，它可能代表了唯一已知的在唾液黏液细胞中选择性表达的基因。我们还将评估Mslg - MUC在粘膜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apomucin的新型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.