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Meibogenesis in Health, Disease, and Aging

健康、疾病和衰老中的Mebogenesis

基本信息

批准号：
10645118
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/10645118
关键词：
Ablation 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 Confusion Cornea Data Development Disease Dry Eye Syndromes Elderly Embryo Environment Enzymes Epidemiology Epithelial Cells Equilibrium Esters Eye Eye diseases Film Future General Population Genes Goals Growth Health Homeostasis Human Hydration status Hypertriglyceridemia Impairment Infant Knockout Mice Knowledge 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 Postembryonic Production Property Proteins Proteomics Quality of life Reaction Regulation Reporting Role Signal Transduction Surface Syndrome Tarsal plate Testing Thick 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 model negative affect novel therapeutic intervention ocular surface postnatal development prenatal timeline 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.

项目概述：我们项目的目标是研究诱导的分子机制，在人和小鼠的睑板中嵌入的睑板腺（MG）中的睑板发生下降。新陈代谢被定义为一系列复杂的分解代谢和合成代谢反应，以及相应的调节代谢。和信号传导机制，导致形成一种叫做睑脂的全分泌分泌物。Meibum是一种独特的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睛健康至关重要，因为它形成了一种保护性的一层，隔离眼睛表面的环境，并提高视力，通过改变折射角膜的性质。正常情况下，睑脂的脂质组成非常保守，这意味着， MG的脂质体内平衡通常受到尚待鉴定的调节机制的严格控制。然而，在这方面，一种称为MG功能障碍（MGD）的MG病理会导致睑脂产生下降或不良变化在其组成中，或两者，对眼表生理学、视力和生活质量产生负面影响，将军MGD是一个主要的促成因素，广泛的条件称为干眼综合征（DES）。MGD DES影响全球高达40%的一般人群，不成比例地影响老年人。此前我们表明小鼠是用于研究痣发生的人MG的可靠模型。使用各种各样的在突变小鼠中，我们已经建立了参与减数分裂的主要基因和酶。但其启动和调节机制仍不清楚。先前在细胞中诱导减数分裂的尝试培养物（例如永生化的人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，我们的目的是阐明减数分裂诱导和衰退的机制，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的动物模型和不同年龄的人类受试者。这些实验应该能让我们确定发育、成熟和老化MG的变化的时间轴，以及一般相关MG转录组，和具体地，以特定酶及其相应的酶的表达水平为基础，脂类产品。将特别考虑同时具有以下特征的基因：1）在MG中高度表达， 2)编码已知控制组织生长、细胞分化和脂质代谢的信号传导因子。在MG和/或其他组织中的稳态，和3）其表达水平在MG和/或其他组织中经历显著变化，开发和老化MG。这些结果将为未来的深入研究提供至关重要的信息 MG生理学的标准和病理学。