Meibogenesis in Health, Disease, and Aging

健康、疾病和衰老中的Mebogenesis

基本信息

批准号：
10444890
负责人：
Igor A Butovich
金额：
$ 41.15万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-30 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10444890
关键词：
Ablation Address Adult Affect Age Aging All-Trans-Retinol Anabolism Animal Model Biological Process Candidate Disease Gene Cell Culture Techniques Cell Differentiation process Cells Characteristics Child Childhood Cholesterol Esters Complex Complex Mixtures Cornea Data Development Disease Dry Eye Syndromes Elderly Embryo Environment Enzymes Epidemiology Epithelial Cells Equilibrium Esters Eye Film Functional disorder Future General Population Genes Goals Growth Health Homeostasis Human Hydration status Hypertriglyceridemia Impairment Infant Knockout Mice Knowledge Lead Link Lipids Literature Longevity Mammals Maps Metabolic Molecular Morphogenesis Mus Mutant Strains Mice Mutation Nature Ocular Pathology Ocular Physiology Organ Organogenesis Pathology Pathway Analysis Pathway interactions Physiological Physiology Production Property Proteins Proteomics Quality of life Reaction Regulation Reporting Role Signal Transduction Surface Syndrome Tarsal plate Testing Thick TimeLine Tissues Vision Waxes Wild Type Mouse age effect age group aqueous base biophysical properties differential expression experimental study gland development histogenesis human model human old age (65+)human subject improved in vivo lipidomics meibomian gland meibomian gland dysfunction molecular marker mouse development mouse model negative affect novel therapeutic intervention ocular surface postnatal development prenatal transcriptome transcriptomics

项目摘要

PROJECT SUMMARY: The goal of our project is to investigate the molecular mechanisms of induction and decline of meibogenesis in Meibomian glands (MG) embedded in tarsal plates of humans and mice. Meibogenesis is defined as an intricate array of catabolic and anabolic reactions, and corresponding regulatory and signaling mechanisms, that lead to formation of a holocrine secretion called meibum. Meibum is a unique lipid secretion that is comprised primarily of extremely long chain and branched wax esters, cholesteryl esters, and a range of other, more complex, compounds. Meibum is vital to the ocular health as it forms a protective layer that isolates the surface of the eye from the environment, and improves vision by changing the refractive properties of the cornea. Lipid composition of meibum is very conservative in normal conditions, implying that lipid homeostasis of MG is typically under tight control of yet to be identified regulatory mechanisms. However, a MG pathology called MG dysfunction (MGD) results in a decline in meibum production, or adverse changes in its composition, or both, negatively affecting the ocular surface physiology, vision, and quality of life in general. MGD is a major contributing factor to a widespread condition called Dry Eye syndrome (DES). MGD and DES affect up to 40% of the general population worldwide, disproportionately affecting elderly. Earlier, we demonstrated that mice are credible models of human MG for studying meibogenesis. Using various lines of mutant mice, we have established major genes and enzymes that are involved in meibogenesis. However, the mechanisms of its initiation and regulation remain unknown. Previous attempts to induce meibogenesis in cell cultures (such as immortalized human MG epithelial cells) failed, as no meibomian lipids have been produced in any tested conditions. Thus, our aim is to elucidate the mechanism of meibogenesis induction and decline in vivo by conducting transcriptomic, lipidomic, immunohistochemical, and physiological characterization of developing and aging MG, using mice that undergo prenatal and postnatal development and aging as primary animal model, and human subjects of different ages. These experiments should allow us to determine a timeline of changes in developing, maturing, and aging MG, and correlate MG transcriptome in general, and key genes of meibogenesis specifically, with the expression levels of specific enzymes and their corresponding lipid products. Special consideration will be given to genes that simultaneously: 1) are highly expressed in MG, 2) encode signaling factors that are already known to control tissue growth, cell differentiation and lipid homeostasis in MG and/or other tissues, and 3) whose expression levels undergo significant changes in developing and aging MG. These results will provide critically important information for future in-depth studies of MG physiology in the norm and pathology.

项目摘要：我们项目的目标是研究诱导和嵌在人类和小鼠睑板中的睑板腺（MG）的睑板生成下降。代谢发生被定义为一系列错综复杂的分解代谢和合成代谢反应，以及相应的调节和信号机制，导致形成称为睑脂的全分泌分泌物。 Meibum 是一个独特的脂质分泌主要由极长链和支链蜡酯、胆固醇酯、以及一系列其他更复杂的化合物。睑脂对眼部健康至关重要，因为它形成了一种保护作用将眼睛表面与环境隔离的层，并通过改变屈光度来改善视力角膜的特性。正常情况下睑脂的脂质成分非常保守，这意味着 MG 的脂质稳态通常受到尚未确定的调节机制的严格控制。然而，称为 MG 功能障碍 (MGD) 的 MG 病理会导致睑脂生成下降或不良变化其成分或两者都会对眼表生理、视力和生活质量产生负面影响一般的。 MGD 是导致干眼症 (DES) 的广泛疾病的一个主要因素。 MGD DES 影响着全球 40% 的普通人口，尤其是老年人。早些时候，我们证明小鼠是研究睑板腺发育的可靠的人类 MG 模型。使用各种线路在突变小鼠中，我们已经建立了参与睑板腺发育的主要基因和酶。然而，其启动和调节机制仍不清楚。先前在细胞中诱导睑板腺发生的尝试培养物（例如永生化人 MG 上皮细胞）失败，因为没有产生睑板脂质在任何测试条件下。因此，我们的目的是阐明诱导和衰退的机制通过进行转录组学、脂质组学、免疫组织化学和生理学表征发育和衰老 MG，使用经历产前和产后发育和衰老的小鼠作为主要对象动物模型和不同年龄的人类受试者。这些实验应该使我们能够确定发展、成熟和衰老 MG 变化的时间线，并总体关联 MG 转录组，以及具体来说，是睑板腺发生的关键基因，以及特定酶的表达水平及其相应的脂质产品。将特别考虑同时满足以下条件的基因：1) 在 MG 中高表达， 2) 编码已知可控制组织生长、细胞分化和脂质的信号因子 MG 和/或其他组织中的稳态，以及 3) 其表达水平发生显着变化发展中和衰老的 MG。这些结果将为未来的深入研究提供至关重要的信息 MG 生理学的正常和病理学。