MicroRNAs and Parotid Acinar Cell Differentiation

描述(申请人提供)：该奖学金项目的长期目标是能够为唾液腺功能丧失的患者提供临床干预。腮腺功能障碍影响着全国数百万人，原因有几个。例如，Sjogren综合症(影响200-400万美国人)会导致腺体功能低下。此外，辐射损伤严重影响腮腺，在接受头颈癌治疗的患者中很常见。患者功能丧失会导致慢性口干症。这导致这些患者的生活质量下降，随着龋齿和牙周病发病率的增加，整体口腔健康也会下降。再生或恢复受损腮腺功能的能力将极大地提高患者的健康和生活质量。这需要进一步了解腺体是如何发育和分化成不同类型的细胞的。明确腮腺分化的分子机制是一个重要的目标。具体地说，腮腺腺泡细胞 负责在副交感神经刺激下产生和分泌唾液蛋白质淀粉酶、腮腺分泌蛋白(PSP)和其他蛋白质。腮腺唾液蛋白有助于抵御细菌和酵母菌，并启动消化。这些细胞高度特化；然而，这种细胞类型的终末分化很差。在过去的十年里，在许多类型的细胞中都发现了microRNAs在发育和分化过程中的重要性。这表明microRNAs是细胞用来控制分化的一种常见机制。然而，microRNAs在腺泡终末分化中的作用还有待研究。在体内，microRNA水平是否与腺泡分化相关，以及哪些microRNA是重要的，这还有待研究。该项目通过两个不同的目标提出假设，即microRNA的表达驱动对腮腺腺泡分化很重要的基因网络。目的一是确定microRNAs在腮腺腺泡细胞分化过程中是否存在差异表达，并与未分化的腺泡细胞进行比较。并确定潜在的microRNA靶基因和网络。将在大鼠腮腺腺泡分化的整个过程中测量microRNA(以及mRNA)的水平，目的是利用生物信息学技术来识别潜在的生物学相关的miRNA：mRNA相互作用和基因调控网络。目的2将通过确定microRNAs是否驱动腮腺腺泡细胞分化相关基因网络的表达来实验测试所预测的相互作用的功能。该项目有助于了解唾液腺生物学的长期目标，从而可以开发临床干预措施来再生或恢复腮腺功能减退患者的腺体。

DESCRIPTION (provided by applicant): The long term goal of this fellowship project is to be able to provide clinical intervention to patients suffering from salivary gland loss of function. Parotid gland dysfunction affects millions of people across the nation, and stems from several causes. Sjogren's syndrome (which affects 2 - 4 million Americans), for instance, results in hypofuction of the gland. Also, radiation damage severely affects the parotid gland and is common among patients receiving treatment for head and neck carcinomas. Loss of function in patients results in chronic xerostomia. This leads to a reduction in quality of life for these patients as well as a reduction in overall oral health as the incidence of dental caries and periodontal disease increases. The ability to regenerate or restore function to damaged parotid glands would greatly increase patient health and quality of life. This requires further knowledge of how the gland develops and differentiates into its different cell types. Defining the molecular mechanisms of parotid differentiation is a significant goal. Specifically, the parotid acinar cells are responsible for producing and secreting the salivary proteins amylase, parotid secretory protein (PSP), and others in response to parasympathetic nerve stimulation. Parotid salivary proteins contribute to defense against bacteria and yeast, and initiation of digestion. These cells are highly specialized; however, the terminal differentiation of this cell type is poorly understoo. Within the last decade, the importance of microRNAs on the process of development and differentiation has been identified in many cell types. This suggests that microRNAs are a common mechanism used by the cell to control differentiation. However, the role of microRNAs in acinar terminal differentiation has yet to be explored. It remains to be investigated if microRNA levels correlate with acinar differentiation in vivo, and which microRNAs are important. This project addresses the hypothesis that microRNA expression drives gene networks that are important for parotid acinar differentiation, through two separate aims. Aim one is to determine if microRNAs are differentially expressed during parotid acinar differentiation in vivo and as compared to undifferentiated acinar cells. And to identify potential microRNA target genes and networks. MicroRNA (and well as mRNA) levels will be measured throughout the course of parotid acinar differentiation in the rat, with the goal of using bioinformatics techniques to identify potentially biologically relevant miRNA:mRNA interactions and gene regulatory networks. Aim 2 will experimentally test the function of the predicted interactions by determining if microRNAs drive expression of differentiation associated gene networks in parotid acinar cells. This project contributes to the long term goal of understanding salivary gland biology to the point that clinical interventions can be developed to regenerate or restore glands to those patients suffering from parotid hypofunction.