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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：
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
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/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&apos 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

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.

项目总结