The regulation of meibomian gland dysfunction by growth hormone and insulin-like

生长激素和类胰岛素对睑板腺功能障碍的调节

• 批准号: 8700036
• 负责人: Juan Ding
• 金额: $ 8.95万
• 依托单位: SCHEPENS EYE RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2015-03-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8700036
• 关键词: Adverse effects; Affect; Age; Aging; American; Androgens; Atrophic; BNIP3L gene; Biological Assay; Cattle; Cell Culture Techniques; Cell Cycle; Cell Cycle Arrest; Cell Death; Cell Proliferation; Cell Survival; Cells; Cessation of life; Data; Dropout; Duct (organ) structure; Ductal; Ductal Epithelium; Enzyme Immunoassay; Epithelial Cells; Exposure to; Eye diseases; Flow Cytometry; Fluorescence Microscopy; Gelatinase B; Generations; Gland; Growth; Growth Hormone Receptor; Hamsters; Histology; Hormones; Human; Insulin; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Interleukin-1; Isotretinoin; Knockout Mice; Literature; Mediating; Mentors; Messenger RNA; Metabolism; Mus; Obstruction; Oryctolagus cuniculus; Pathway interactions; Phase; Play; Procedures; Proteins; Publishing; Quality of life; RNA Interference; Regulation; Risk Factors; Role; Sebaceous Glands; Signal Pathway; Signal Transduction; Signaling Protein; Somatotropin; TNFSF10 gene; Testing; Transgenic Mice; Translating; Tretinoin; Viscosity; Wild Type Mouse; base; effective therapy; eye dryness; human FRAP1 protein; human GHR protein; keratinization; mRNA Expression; meibomian gland; meibomian gland dysfunction; mouse model; proline-rich proteins; public health relevance; receptor

ABSTRACT Meibomian gland dysfunction (MGD) is believed to be the leading cause of dry eye disease, which affects the quality of life of millions of people in the US. MGD is characterized by terminal excretory duct obstruction, hyperkeratinization of the ductal epithelium, increased viscosity of meibum and meibomian gland atrophy/dropout. Currently the mechanism of MGD is not known. Risk factors include old age, androgen deficiency and exposure to 13-cis retinoic acid (RA). Given that RA causes prototypical MGD, I propose to study the mechanism of MGD using human meibomian gland cell cultures and mouse models exposed to RA. I hypothesize that RA inhibits meibomian gland cell proliferation and induces cell death by affecting specific intracellular pathways and upregulating specific death-inducing proteins. In addition, I hypothesize that RA promotes meibomian gland keratinization via specific keratinization-related proteins. To counteract RA-induced MGD, I propose to use two hormones, growth hormone (GH) and insulin-like growth factor-1 (IGF-1). GH/IGF-1 is well-known to promote cell proliferation and cell survival, and plays roles in the proliferation and differentiation of other types of sebaceous gland cells. I hypothesize that GH/IGF-1 signaling intersects the RA-induced signaling pathways and antagonizes the protein changes involved in proliferation, cell death and keratinization. To test my hypotheses, I will use a variety of experimental procedures, including human cell cultures, immunoassays, enzyme assays, qRT-PCR, RNA silencing, fluorescence microscopy, flow cytometry, mouse models, histology and hormone treatments. My specific aims are to: 1) determine the mechanism by which 13-cis RA induces cell cycle arrest, cell death and keratinization in immortalized human meibomian gland epithelial cells; 2) elucidate how GH/IGF-1 interrupts the generation of these 13-cis RA-induced cellular sequelae; 3) examine the meibomian gland histology in mice with altered GH signaling; 4) determine the effect of 13-cis RA on inducing MGD including gland atrophy and ductal hyperkeratinization in wild type (WT) mice; and 5) determine the effect of topical treatment with GH/IGF-1 on 13-cis RA induced MGD in WT mice. My long-term objective is to better understand the mechanism of MGD and to translate this information into a potential treatment for MGD.

摘要 睑板腺功能障碍（MGD）被认为是干眼症的主要原因 疾病，影响了美国数百万人的生活质量。MGD的特征在于： 末端排泄管阻塞，导管上皮角化过度，增加 睑板腺萎缩/脱落。目前，MGD的机制是 不知道。危险因素包括年老、雄激素缺乏和接触13-顺式维甲酸 酸（RA）。鉴于类风湿性关节炎导致典型的MGD，我建议研究MGD的机制 使用人睑板腺细胞培养物和暴露于RA的小鼠模型。我假设 RA抑制睑板腺细胞增殖并通过影响特定的 细胞内途径和上调特定的死亡诱导蛋白。另外我 假设RA通过特异性角化相关蛋白促进睑板腺角化 proteins. 为了对抗RA诱导的MGD，我建议使用两种激素，生长激素（GH） 和胰岛素样生长因子-1（IGF-1）。众所周知，GH/IGF-1促进细胞增殖， 细胞存活，并在其他类型的皮脂腺细胞的增殖和分化中发挥作用。 腺细胞我推测GH/IGF-1信号与RA诱导的信号通路交叉 并拮抗与增殖、细胞死亡和角化有关的蛋白质变化。到 为了验证我的假设，我将使用各种实验程序，包括人类细胞 培养、免疫测定、酶测定、qRT-PCR、RNA沉默、荧光显微镜检查， 流式细胞术、小鼠模型、组织学和激素治疗。 本论文的主要目的是：1）确定13-cis RA诱导细胞凋亡的机制。 永生化人睑板腺上皮细胞周期阻滞、细胞死亡和角化 2）阐明GH/IGF-1如何中断这些13-顺式RA诱导的细胞的产生 后遗症; 3）检查具有改变的GH信号传导的小鼠中的睑板腺组织学; 4） 确定13-顺式RA对诱导MGD（包括腺体萎缩和导管萎缩）的作用， 5）确定用以下物质局部治疗的效果： GH/IGF-1对WT小鼠中13-顺式RA诱导的MGD的影响。我的长期目标是更好 了解MGD的机制，并将这些信息转化为潜在的治疗方法 关于MGD