Defining mechanisms driving dry eye disease progression

定义驱动干眼病进展的机制

• 批准号: 10458017
• 负责人: Sarah Monica Knox
• 金额: $ 39.77万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10458017
• 关键词: Anterior; Anti-Inflammatory Agents; Autoimmune; Automobile Driving; Awareness; Cell Differentiation process; Cell Lineage; Cell Nucleus; Cells; Chronic; Clinical; Cornea; Corneal Diseases; Data; Development; Diagnostic; Disease; Disease Progression; Dry Eye Syndromes; Early Diagnosis; Early Intervention; Endothelial Cells; Epithelial; Epithelial Cells; Exocrine Glands; Eye; Eye diseases; Generations; Genetic; Genetic Variation; Goals; Heterogeneity; Homeostasis; Human; Hyperplasia; Impairment; Inbred BALB C Mice; Infiltration; Inflammation; Inflammatory; Lacrimal gland structure; Life; Lupus; Maps; Mediating; Modeling; Molecular; Morbidity - disease rate; Mus; Neural Crest; Onset of illness; Organ; Outcome; Outcome Study; Pathologic; Patients; Population; Process; Rheumatoid Arthritis; Signal Pathway; Signal Transduction; Sjogren' s Syndrome; Stromal Cells; Therapeutic; Therapeutic Intervention; Tissues; aqueous; base; cell type; corneal epithelium; curative treatments; driving force; efficacious treatment; eye dryness; gene network; innovation; insight; limbal; microbial; mouse model; nerve supply; new technology; new therapeutic target; novel; ocular surface; prevent; repaired; self-renewal; stem; stem cell population; stem cells; stem-like cell; stromal progenitor; systemic autoimmune disease; therapeutic development; transcriptome sequencing; treatment strategy

PROJECT SUMMARY Aqueous-deficient dry eye is among the most common and debilitating clinical manifestations of systemic autoimmune diseases such as Sjögren's, lupus and rheumatoid arthritis. While it is well established that chronic inflammation of the ocular surface and exocrine glands (e.g., lacrimal gland) represents the predominant driving force in autoimmune-mediated dry eye disease, pathological alterations in the cornea are among the most common and debilitating clinical manifestations. With the cornea providing approximately two- thirds of the eye's focusing power and protecting the anterior eye from environmental, inflammatory and microbial insult, disease-mediated corruption of tissue function and homeostasis has a vast array of pathological outcomes. Indeed, a multitude of studies in both human patients and mouse models of aqueous- deficient dry eye illustrate late stage disease encompasses epithelial barrier disruption, epithelial hyperplasia, reduced corneal innervation and inflammatory cell infiltration. Thus, dry eye disease induces pathological changes along multiple levels. However, due to the limited understanding of the cellular makeup of the cornea, including the lineage relationships of specific cell types, the impact of dry eye on cell heterogeneity and lineage outcomes is unknown. To help solve this significant problem, we have begun to define the cellular diversity and differentiation trajectories of corneal cells and how these are perturbed by dry eye disease using single cell nuclei RNAsequencing in combination with the autoimmune regulatory (Aire)-deficient mouse model. Using this model, we have also begun to identify novel changes in corneal cell composition during the emergence of dry eye that may underlie disease development and progression. Based on these data we hypothesize that disease progression is promoted by an alteration in corneal cell fate that compromises the repair and cellular replenishment of the tissue. We propose to explore this hypothesis by first defining epithelial and stromal cell heterogeneity, differentiation trajectories and stem/progenitor cells in the homeostatic cornea. We will then seek to elucidate the mechanisms by which dry eye disease development impacts the self-renewal, differentiation capacity and function of corneal cells during dry eye disease development. Outcomes from these studies will aid in the development of therapeutics to halt disease progression, as well as the generation of diagnostic targets for early intervention.

项目总结 缺水干眼是全身性干眼症最常见和最令人衰弱的临床表现之一。 自身免疫性疾病，如干燥综合征、狼疮和类风湿性关节炎。虽然公认的是 眼表和外分泌腺(如泪腺)的慢性炎症代表 自身免疫介导的干眼病的主要驱动力是角膜的病理改变 最常见和最令人衰弱的临床表现之一。角膜提供了大约两个- 3/3的眼睛聚焦力并保护前眼免受环境、炎症和 微生物伤害、疾病介导的组织功能破坏和动态平衡有大量的 病理结果。事实上，在人类患者和小鼠模型房水中进行的大量研究- 缺乏干眼说明晚期疾病包括上皮屏障破坏，上皮增生， 角膜神经支配减少，炎性细胞浸润减少。因此，干眼病会导致病理性 沿多个级别进行更改。然而，由于对角膜细胞组成的了解有限， 包括特定细胞类型的谱系关系、干眼症对细胞异质性和谱系的影响 结果还不得而知。为了帮助解决这一重大问题，我们已经开始定义细胞多样性和 利用单细胞研究干眼病对角膜细胞分化轨迹的影响 与自身免疫调节(AIRE)缺陷小鼠模型相结合的核RNA测序。使用这个 模型中，我们也开始发现在干性角膜出现期间角膜细胞成分的新变化 眼睛可能是疾病发生和发展的基础。根据这些数据，我们假设 疾病的进展是由角膜细胞命运的改变促进的，这种改变损害了修复和细胞 组织的补充。我们建议通过首先定义上皮细胞和基质细胞来探索这一假说 动态平衡角膜中的异质性、分化轨迹和干/祖细胞。到时候我们会的 试图阐明干眼病发展影响自我更新的机制， 干眼病发生发展过程中角膜细胞的分化能力和功能。这些措施的结果 研究将有助于开发治疗方法来阻止疾病的进展，以及产生 早期干预的诊断目标。