Defining mechanisms driving dry eye disease progression

定义驱动干眼病进展的机制

基本信息

批准号：
10290035
负责人：
Sarah Monica Knox
金额：
$ 41万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
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/10290035
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 Genes 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&apos s Syndrome Stromal Cells Therapeutic Therapeutic Intervention Tissues aqueous base cell type corneal epithelium curative treatments driving force efficacious treatment eye dryness 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

项目摘要

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.

项目摘要缺乏水性的干眼是全身性最常见和令人衰弱的临床表现之一 Sjögren，狼疮和类风湿关节炎等自身免疫性疾病。虽然已经确定了眼表和外分泌腺的慢性炎症（例如，泪腺）代表自身免疫性介导的干眼病中的主要驱动力，角膜的病理改变是最常见和令人衰弱的临床表现。角膜提供大约两个眼睛的三分之一的聚焦力和保护前眼免受环境，炎症和微生物侮辱，疾病介导的组织功能的损坏和稳态有很多病理结果。实际上，在人类患者和水性的小鼠模型中的许多研究不足的干眼说明后期疾病包括上皮屏障破坏，上皮增生，角膜神经支配减少和炎症细胞浸润。那就是干眼症诱导病理学沿多个级别的变化。但是，由于对角膜细胞构成的了解有限，包括特定细胞类型的谱系关系，干眼对细胞异质性和谱系的影响结果未知。为了帮助解决这个重大问题，我们开始定义细胞多样性和角膜细胞的分化轨迹以及如何使用单细胞干燥眼部疾病扰动这些轨迹核与自身免疫调节（AIRE）缺陷小鼠模型结合使用。使用此模型，我们还开始确定干燥出现期间角膜细胞组成的新变化可能是疾病发展和进展的眼睛。基于这些数据，我们假设疾病进展是通过损害修复和细胞的角膜细胞命运的改变来促进的补充组织。我们建议通过首先定义上皮和基质细胞来探讨这一假设稳态角膜中的异质性，分化轨迹和茎/祖细胞。然后我们会寻求阐明干眼症发育影响自我更新的机制，在干眼症发育过程中，角膜细胞的分化能力和功能。这些结果研究将有助于发展理论以阻止疾病进展，并产生早期干预的诊断目标。