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Role of lacrimal gland myoepithelial cells in dry eye disease

泪腺肌上皮细胞在干眼病中的作用

基本信息

批准号：
10553199
负责人：
DRISS ZOUKHRI
金额：
$ 48.38万
依托单位：
TUFTS UNIVERSITY BOSTON
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10553199
关键词：
Acinar Cell Acinus organ component Actins Age Animal Model Atrophic Autoimmune Candidate Disease Gene Catabolism Cell Separation Cell physiology Cells Chronic Contractile Proteins Contracts Coupling Data Denervation Disease Down-Regulation Dry Eye Syndromes Ductal Epithelial Cell Efferent Neurons G-Protein-Coupled Receptors GTP-Binding Proteins Gene Expression Genes Gland Goals Health Human Impairment In Vitro Inflammation Inflammatory Interleukin-1 Knock-out Knowledge Lacrimal gland structure Lead MAPK8 gene MMP2 gene Mammary gland Mediating Metalloproteases Microfilaments Molecular Mus Muscle Muscle Proteins Muscle denervation procedure Muscular Atrophy Myoepithelial cell N-terminal Neuropeptides Output Oxytocin Oxytocin Receptor Pathogenesis Pathway interactions Phosphotransferases Process Production Proteins Proteomics RNA Receptor Cell Receptor Signaling Reporting Role Second Messenger Systems Signal Transduction Signal Transduction Pathway Sjogren&apos s Syndrome Smooth Muscle Smooth Muscle Myocytes Sorting Stress System Techniques Tissues Translating Ubiquitin aqueous calponin cell type cytokine mammary milk production milk secretion multicatalytic endopeptidase complex muscular system neural neurotransmitter release new therapeutic target novel protein expression receptor receptor expression response sex transcriptome sequencing

项目摘要

Chronic inflammation of the lacrimal gland (LG), as occurs in Sjögren’s syndrome, is the leading cause of aqueous- deficient dry eye disease (DED). The mechanisms leading to insufficient LG secretion are still not completely understood. The LG is composed of acinar, myoepithelial, and ductal cells, with acini and myoepithelial cells (MEC) forming the secretory units. MECs express several muscle proteins, such as alpha smooth muscle actin (SMA) and calponin, and are therefore able to contract. MECs are best studied in the mammary gland where their contraction is shown to be crucial for milk production and contraction is mainly controlled by the neuropeptide oxytocin. Despite their potential critical role in LG secretion, very little is known about MEC contraction in this tissue, nor is the impact of chronic inflammation of the LG on these cells. One of goals of the current proposal is to fill this gap in knowledge. Our preliminary studies show that murine and human LG MECs express the oxytocin receptor (OXTR) and contract in response to oxytocin stimulation. Furthermore, we show that MECs in chronically inflamed LG are atrophied, with down-regulation of contractile proteins SMA and calponin and the OXTR and MECs from these glands do not contract in response to oxytocin stimulation. We previously reported that interleukin-1 (IL-1) inhibits neurotransmitter release from LG efferent nerves leading to DED. We also reported activation of the stress activated c-Jun N-terminal kinase (JNK) and metalloproteinases 2 (MMP2) in chronically inflamed LGs and that inhibition of either pathway restored LG secretion and tears output in animal models of DED. Numerous studies showed that denervation of muscle tissues leads to tissue atrophy and degradation of muscle contractile proteins via the ubiquitin/proteasome pathways. Based on these findings, we hypothesize that in chronic DED, proinflammatory cytokines inhibit neurotransmitter release from LG efferent nerves creating a denervated-like tissue and that they trigger degradation of the OXTR and MEC myofilament proteins. This degradation translates into a loss of contractibility of MECs thus further exacerbating the effect of the loss of neural input on the secretory units of the LG. We further hypothesize that the JNK, MMP2, and ubiquitin/proteasome pathways mediate the effects of proinflammatory cytokines on MEC functions. We will use both in vitro (sorted MEC cells) as well as animal models of DED to investigate how proinflammatory cytokines interfere with oxytocin-induced contraction of LG MECs. We will use unbiased RNA-seq and quantitative global proteomics techniques to identify novel pathways that are altered in MECs in chronically inflamed LGs. At the completion of these studies, we will have established a role for the MEC, an important and yet understudied cell in the LG, and the oxytocin signaling system in the pathogenesis of aqueous-deficient DED and identified potential novel therapeutic targets.

泪腺（LG）的慢性炎症，如Sjögren综合征，是导致含水性流泪的主要原因