Modifying the extracellular matrix to prevent dry eye disease and age-related Meibomian gland dysfunction (ARMGD)

修改细胞外基质以预防干眼病和与年龄相关的睑板腺功能障碍 (ARMGD)

• 批准号: 10612973
• 负责人: Vivien Jane Coulson-Thomas
• 金额: $ 40.19万
• 依托单位: UNIVERSITY OF HOUSTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10612973
• 关键词: 1 year old; 2 year old; 5 year old; Age; Aging; Anabolism; Atrophic; Basal Cell; Binding; Biodistribution; Biological Availability; Blurred vision; Cell Proliferation; Clinic; Clinical; Clinical Research; Complex; Data; Desiccation; Development; Dry Eye Syndromes; Dryness; Enzymes; Esthesia; Esthetics; Etiology; Extracellular Matrix; Eye; Eyelid Diseases; FDA approved; Fatigue; General Population; Gland; HAS2 gene; HAS3 gene; Homeostasis; Human; Hyaluronan; Individual; Knockout Mice; Life; Lipids; Medical Care Costs; Modeling; Mus; Pain; Pathogenesis; Pathology; Photophobia; Physiological; Population; Predisposition; Prevalence; Production; Productivity; Proliferating; Protein Isoforms; Publishing; Quality of life; Resistance; Stress; Symptoms; Tarsal plate; Techniques; Testing; Time; Tissues; Treatment Protocols; United States; Up-Regulation; Wild Type Mouse; Work; age related; aged; design; extracellular; eye dryness; gland development; hyaluronan synthase 1; innovation; insight; macromolecule; meibomian gland; meibomian gland dysfunction; novel strategies; novel therapeutic intervention; novel therapeutics; overexpression; prevent; progenitor; stem cell fate specification; stem cells; subcutaneous; therapy development; translational potential

Project summary The prevalence of dry eye disease (DED) ranges from ~5 to 50% of the general population with an estimated US$ 3.8 billion dollars in associated medical costs. Symptoms of DED include pain, fatigued and/or sore eyes, photophobia and blurred vision, which lead to a decrease in productivity and reduce the quality of life. Unfortunately, treatment options for DED are limited. Clinical studies suggest 85% of overall DED cases are caused by Meibomian gland dysfunction (MGD). As humans and mice age, their Meibomian glands (MGs) undergo age-related changes, including decreased acinar basal cell proliferation and atrophy, and these changes result in age related-MGD (ARMGD). The precise cause of ARMGD remains elusive, which makes the development of therapies extremely challenging. Hyaluronan (HA) is a major extracellular component that interacts and binds to a myriad of molecules forming complex macromolecules which regulate major physiological functions, such as development and stem cell specification. Our recently published work shows that compound HA synthase (Has)-1 and -3 null mice, namely Has1-/-;Has3-/- mice, have enlarged MGs when compared to age matched wild-type (wt) mice. Our preliminary data show that the MGs of Has1-/-;Has3-/- mice continue to increase in size throughout life, and, interestingly, these mice do not develop ARMGD. At 1 year of age, Has1-/-;Has3-/- mice have a striking 4-fold increase in MG volume and an overall 10-fold increase in lipid production, compared to age matched wt mice. We hypothesize that the increase in HA expression in and around the MGs of Has1-/-;Has3-/- mice is capable of maintaining viable progenitor cells as they age, which in turn prevents ARMGD. Specific aim 1 of this proposal will characterize the extracellular matrix in the MGs of wt and Has1-/-;Has3-/- mice with a focus on the composition of the HA matrix. Specific aim 2 of this proposal will analyze the distribution of MG progenitor and proliferating cells in order to identify how the MGs of Has1- /-;Has3-/- mice enlarge over time. This aim will also characterize the lipid composition of the meibum, and verify whether enlarged glands can prevent DED. Importantly, although Has1-/-;Has3-/- mice lack two isoforms of the enzyme responsible for HA biosynthesis, they up-regulate the third isoform (Has2), and, in turn, present a significant increase in HA expression in and around MGs when compared to wt mice. Therefore, we also hypothesize that increasing Has2 expression and HA bioavailability within MGs could prevent ARMGD in aged wt mice. Specific aim 3 will test whether Has2 overexpression and FDA approved HA-based treatment regimens to increase the bioavailability of HA within tarsal plates and MGs can prevent ARMGD in wt mice.

项目摘要 干眼症（DED）的患病率范围为一般人群的约5%至50%， 估计相关医疗费用为38亿美元。DED的症状包括疼痛，疲劳， 和/或眼睛疼痛，恐惧症和视力模糊，这导致生产力下降， 生活质量不幸的是，DED的治疗选择有限。临床研究表明，85%的 DED病例是由睑板腺功能障碍（MGD）引起的。随着人类和小鼠的衰老， 腺体（MG）经历年龄相关的变化，包括腺泡基底细胞增殖减少和萎缩， 这些变化导致年龄相关性MGD（ARMGD）。造成这一局面的确切原因仍然难以捉摸， 这使得治疗的发展极具挑战性。 透明质酸（HA）是一种主要的细胞外组分，其与多种细胞因子相互作用并结合。 分子形成复杂的大分子，调节主要的生理功能，如 发育和干细胞特化。我们最近发表的工作表明，复合HA合酶 （Has）-1和-3缺失小鼠，即Has 1-/-; Has 3-/-小鼠，与年龄匹配的小鼠相比，MG增大。 野生型（wt）小鼠。我们的初步数据显示，Has 1-/-; Has 3-/-小鼠的MG持续增加， 有趣的是，这些小鼠不会发展为ARMGD。1岁时，具有1-/-;具有3-/- 小鼠的MG体积显著增加4倍，脂质产生总体增加10倍， 与年龄匹配的野生型小鼠相比。我们假设，HA表达的增加，以及周围的 Has 1-/-; Has 3-/-小鼠的MG能够随着年龄的增长而维持活的祖细胞，这反过来 防止ARMGD。本提案的具体目标1将表征野生型MG中的细胞外基质 和Has 1-/-; Has 3-/-小鼠，重点是HA基质的组成。本提案的具体目标2 将分析MG祖细胞和增殖细胞的分布，以确定Has 1- /-; Has 3-/-小鼠随时间增大。该目的还将表征睑脂的脂质组成，并且 验证是否扩大腺体可以防止DED。重要的是，尽管Has 1-/-; Has 3-/-小鼠缺乏两个 在负责HA生物合成的酶的同种型中，它们上调第三种同种型（Has 2），并且，在 反过来，与野生型小鼠相比，MG中和周围的HA表达显著增加。 因此，我们还假设MG中增加Has 2表达和HA生物利用度可以 防止老龄野生型小鼠的ARMGD。具体目标3将测试Has 2过表达和FDA是否批准 以HA为基础的治疗方案，以增加HA在睑板和MG内的生物利用度，可以预防 野生型小鼠中的ARMGD。