Meibogenesis in Health, Disease, and Aging

健康、疾病和衰老中的Mebogenesis

• 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
• 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

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：我们项目的目的是研究诱导的分子机制和 在人类和小鼠的tarsal板中嵌入的Meibomian腺体（MG）中的造物生成下降。 Meibibogenese的定义为复杂的分解代谢和合成代谢反应阵列，以及相应的调节 和信号传导机制，导致形成了称为meibum的全体分泌物。 meibum是一个独特的 脂质分泌主要由极长的链和分支蜡酯，胆固醇酯， 以及其他一系列更复杂的化合物。 Meibum对眼部健康至关重要，因为它形成了保护性 将眼表与环境隔离的层，并通过更改折射来改善视力 角膜的特性。在正常情况下，梅布姆的脂质组成非常保守，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， 一种称为MG功能障碍（MGD）的MG病理学导致Meibum生产下降或不良变化 在其组成中，或两者兼有对眼表面生理，视力和生活质量的负面影响 一般的。 MGD是称为干眼综合征（DES）的广泛疾病的主要因素。 MGD DE会影响全世界多达40％的普通人群，对老年人产生不成比例的影响。早些时候，我们 证明小鼠是人类MG的可信模型，用于研究肠裂。使用各种行 突变小鼠，我们已经建立了参与Meibibogeny的主要基因和酶。但是， 其启动和调节的机制仍然未知。以前试图在细胞中诱导Meibibogeny的尝试 培养物（例如永生的人类MG上皮细胞）失败了，因为没有产生Meibomian脂质 在任何经过​​测试的条件下。因此，我们的目的是阐明诱导和下降的机制 通过进行转录组，脂质组，免疫组织化学和生理特征的体内体内 开发和衰老的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。这些实验应该使我们能够确定 开发，成熟和衰老MG以及一般相关的MG转录组的时间表 特定酶的表达水平及其相应 脂质产品。对同时的基因进行特殊考虑：1）在mg中高度表达， 2）编码已经已知可以控制组织生长，细胞分化和脂质的信号传导因子 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 开发和衰老MG。这些结果将为未来的深入研究提供至关重要的信息 在规范和病理学中的MG生理学。