LACRIMAL GLAND BIOINFORMATICS: A NEURAL CONNECTION OF DRY EYE AND AGING

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 与年龄相关的泪腺功能和结构的改变被认为是由于副交感神经支配的进行性减少所致。其目的是识别在衰老和实验性失神经干眼模型中共同发现的受影响的基因，并阐明随年龄变化的细胞网络以及那些显示神经特异性调节的细胞网络。 我们发现随着年龄的增长，软骨来源的维甲酸敏感蛋白，也被称为黑色素瘤抑制活性(MIA)蛋白的表达增加。在骨关节炎和类风湿关节炎患者的血清和滑液中发现MIA的表达增加。MIA家族的两个相关成员MIA2和MIA3在老年泪腺中仅有MIA2的表达和增加。免疫组织化学分析发现MIA主要定位于小叶导管内，腺泡内有少量染色。为了研究泪腺MIA表达的神经控制，我们进行了副交感神经和交感神经的去神经治疗。实时逆转录聚合酶链式反应、蛋白质印迹分析和免疫组织化学分析显示，4个月或24个月组的对照组和失神经支配组之间没有显著差异。 由于MIA家族的成员可能是与泪腺免疫状况改变相关的许多因素之一，因此也选择了从基因芯片结果中发现的在老化和失神经的泪腺中丰富的促炎基因，并进行了实时RT-PCR分析。MetaCore系统生物学平台被用来识别不同神经条件下常见和独特的促炎基因，以及那些显示性别特异性表达的基因。利用这些结果，我们在MIA和MIA2的背景下产生了一个调控网络，其中包括caspase 1、IL-1β、转化生长因子β-1、细胞间黏附分子-1、血管黏附分子-1和膜联蛋白(A1、A3、A5)。表达数据的子网络和转录调控的子网络是基于先验知识生成的，并使用基因本体丰富来解释。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Age related changes in the function and structure of the tears producing lacrimal gland is postulated to be contributed by progressive reduction in parasympathetic innervation. The goal is to identify affected genes that are found in common in aging and experimental denervated dry eye model, and to elucidate cellular networks that are altered with age and those that displayed neural-specific regulation. We have found increased expression of cartilage derived-retinoic acid-sensitive protein, also known as melanoma inhibitory activity (MIA) protein with age. Increased expression of MIA has been found in serum and synovial fluid in patients with osteoarthritis and rheumatoid arthritis. Two related members of the MIA family, MIA2 and MIA3, were also examined, and only MIA2 were found expressed and increased in aged lacrimal gland. Immunohistochemical analysis found MIA localized predominantly to intralobular ducts, with sparse staining in acini. To investigate the neural control of MIA expression in the lacrimal gland, we carried out parasympathetic and sympathetic denervation. Real-time RT-PCR, western blot analysis, and immunohistochemical analysis did not reveal significant differences between the controls and denervated in the 4 months or 24 months group. Since members of the MIA family may be one of many factors associated with the altered immune condition in the lacrimal gland, proinflammatory genes that were found enriched in aged and denervated lacrimal glands from microarray results were also selected and analyzed by real time RT-PCR analysis. The MetaCore systems biology platform was used to identify common and unique proinflammatory genes under different neural conditions, as well as those genes that displayed gender-specific expression. Using these results, we generated a regulatory network in the context of MIA and MIA2, and consist of, among others, caspase 1, interleukin-1 beta, transforming growth factor beta -1, intercellular adhesion molecule-1, vascular adhesion molecules-1, and annexin (A1, A3, A5). Sub-networks of expression data and sub-networks of transcription regulation were generated based on a priori knowledge and interpreted using gene ontology enrichment.