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

泪腺生物信息学：干眼症与衰老的神经联系

• 批准号: 7381346
• 负责人: DOAN M NGUYEN
• 金额: $ 15.18万
• 依托单位: LOUISIANA STATE UNIV A&M COL BATON ROUGE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7381346
• 关键词: LACRIMAL; GLAND; BIOINFORMATICS; NEURAL; CONNECTION

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. The lacrimal gland (LG) and the ocular surface are intimately linked through the central nervous system by sensory and peripheral autonomic neural systems. Nerve activity controls LG secretory response, and a constant parasympathetic input from the ocular surface to the LG is required for maintenance of the ocular surface homeostasis. Aging is associated with decreased corneal sensation and, therefore, with a decrease in response and sensitivity by the LG. Removal of the interaction between the cornea and LG, by eliminating the parasympathetic input to secretion, resulted both in structural and functional alteration in the LG. Dry eye and corneal ulcer also developed on the experimental side. In the LG, the expression of genes associated with the endoplasmic reticulum (ER) activity was down-regulated, suggesting a deficiency in protein quality control; conversely, the upregulated expressions of proinflammatory cytokines and chemokines suggest an alteration in the immune homeostasis. It is the hypothesis of this proposal that the progressive decline in neural activation of secretion that occurs with age is associated with loss of sensitivity to muscarinic, parasympathetic stimulation critical for the maintenance of LG ER integrity and gene expression. The second hypothesis of this proposal is that in response to stimulation, the LG demonstrates deficiency in the ER-stress response. The identification of age-related genes and patterns of gene expression will elucidate the underlying mechanisms responsible for the observed morphologic and functional alterations, as well as marker genes that may be relevant for diagnostic and therapeutic treatment of dry eye in the elderly. To gain a better understanding of the molecular effects of aging on this system, and to identify age-related changes in expression of these classes of genes, we propose: Specific Aim I: To determine age-associated gene expression in rat lacrimal gland tissues. Specific Aim II: To investigate the role of known transcriptional factors in the regulation of age-specific gene expression. Functional related genes share common transcriptional regulatory elements in their promoters. Patterns of gene expression will reveal a limited numbers of transcription factors (ATF6, XBP-1, NF-Y, CHOP, NF?B) that may be altered in the aged LG. Analysis of gene expression patterns to co-regulations is better visualized using bioinformatics approaches. Specific Aim III: To investigate the parasympathetic-mediated intracellular signaling pathways in the modulation of ER-stress and proinflammatory responses in aged LG acini.

该子项目是利用 NIH/NCRR 资助的中心拨款提供的资源的众多研究子项目之一。子项目和研究者 (PI) 可能已从另一个 NIH 来源获得主要资金，因此可以在其他 CRISP 条目中得到体现。列出的机构是中心的机构，不一定是研究者的机构。泪腺（LG）和眼表通过中枢神经系统通过感觉和周围自主神经系统紧密相连。神经活动控制 LG 分泌反应，并且需要从眼表面到 LG 的持续副交感神经输入来维持眼表面稳态。衰老与角膜感觉下降有关，因此与角膜反应和敏感度下降有关。通过消除副交感神经的分泌输入，消除角膜和 LG 之间的相互作用，从而导致 LG 的结构和功能发生改变。实验侧也出现干眼症和角膜溃疡。在 LG 中，与内质网 (ER) 活性相关的基因表达下调，表明蛋白质质量控​​制存在缺陷；相反，促炎细胞因子和趋化因子表达上调表明免疫稳态发生改变。该提议的假设是，随着年龄的增长，神经分泌激活的逐渐下降与对毒蕈碱、副交感神经刺激的敏感性丧失有关，而副交感神经刺激对于维持 LG ER 完整性和基因表达至关重要。该提议的第二个假设是，在对刺激的反应中，LG 表现出 ER 应激反应的缺陷。年龄相关基因和基因表达模式的鉴定将阐明导致观察到的形态和功能改变的潜在机制，以及可能与老年人干眼的诊断和治疗相关的标记基因。为了更好地了解衰老对该系统的分子影响，并确定这些类别基因的表达与年龄相关的变化，我们建议： 具体目标 I：确定大鼠泪腺组织中与年龄相关的基因表达。 具体目标二：研究已知转录因子在年龄特异性基因表达调节中的作用。功能相关基因在其启动子中共享共同的转录调控元件。基因表达模式将揭示有限数量的转录因子（ATF6、XBP-1、NF-Y、CHOP、NF?B），这些转录因子可能在老年 LG 中发生改变。使用生物信息学方法可以更好地可视化基因表达模式与共同调控的分析。 具体目标 III：研究副交感神经介导的细胞内信号通路在老年 LG 腺泡中内质网应激和促炎反应调节中的作用。