补体C1q/肿瘤坏死因子相关蛋白3在唾液腺组织的表达和抗凋亡功能研究

Complement C1q/tumor necrosis factor-related protein 3 (CTRP3) is a bioactive factor found in recent years. Its expression and function in the salivary gland has not yet been reported. On basis of our preliminary experiments, we hypothesize that salivary gland is the new source producing CTRP3 and the new target for CTRP3. We will characterize the expression and distribution of CTRP3 in rat, mouse and human salivary glands and rat SMG-C6 cell line, and detect the content of CTRP3 in human saliva and supernatant of SMG-C6 cells. By using the TNF-α-induced apoptosis model of SMG-C6 cells, we will determine the anti-apoptotic function of CTRP3 on salivary epithelial cells. By exploring PI3K/Akt and/or ERK1/2-mediated signal transduction pathways, we will further investigate the mechanism of anti-apoptotic function of CTRP3. This study will comprehensively reveal the properties of expression, distribution, secretion, function and mechanism of CTRP3 in the salivary gland. It will help to enrich the understanding of biological function of CTRP3 and provide a novel insight into a future therapeutic target for hypofunction of salivary glands.

补体C1q/肿瘤坏死因子相关蛋白3（CTRP3）是近年发现的一种生物活性因子，其在唾液腺中的表达和功能目前尚未见报道。在预实验的基础上，本课题提出如下科学设想：唾液腺是产生CTRP3的新来源，亦是CTRP3作用的新靶点。我们拟以CTRP3在唾液腺中的表达特性和抗凋亡作用为重点，检测CTRP3在啮齿类动物和人唾液腺组织及大鼠唾液腺腺上皮细胞系SMG-C6中的表达和分布特点、检测人唾液及细胞培养上清中CTRP3的含量；以TNF-α诱导的SMG-C6细胞凋亡为模型，明确CTRP3抗唾液腺腺上皮细胞凋亡的功能；以PI3K/Akt和/或ERK1/2信号转导途径为中心，揭示CTRP3抗腺上皮细胞凋亡的作用机制。以上研究将从表达、分布、分泌、功能及机制五方面全面研究CTRP3在唾液腺中的功能性表达，不仅有助于丰富对CTRP3生物学功能的认识，也为以抗腺上皮细胞凋亡为靶点防治唾液腺分泌功能低下提供新的思路

CTRP3在许多组织中存在表达，在代谢、细胞增殖和炎症反应中起着关键作用，然而CTRP3在唾液腺中的表达模式和功能尚不清楚。项目研究证实了人、大鼠和小鼠的下颌下腺和腮腺中均可检测到CTRP3 mRNA和蛋白的表达，并阐明了其分布特点。在功能上，在SMG-C6细胞系及人下颌下腺组织块中，CTRP3预孵育可促进TNF-α诱导的细胞凋亡。在机制上，SMG-C6细胞系中，TNF-α降低了经上皮细胞电阻，增加了葡聚糖的流量，降低了claudin-3的表达；CTRP3预孵育促进了TNF-α诱导的上述变化，同时也诱导了claudin-1和claudin-4的降低；CTRP3可通过增加TNFR1的表达和促凋亡通路活性从而促进TNF-α诱导的凋亡；提示TNFR1及其下游促凋亡通路是CTRP3发挥促炎性凋亡的重要环节。在舍格伦综合征患者及动物模型中，CTRP3表达上升，综合体外CTRP3促进TNF-α介导的凋亡和屏障功能障碍，进一步提示CTRP3可能参与舍格伦综合征的发病过程。