Targeting Fibroblast Growth Factor Signaling as a New Therapeutic Strategy for Meibomian Gland Dysfunction

靶向成纤维细胞生长因子信号作为睑板腺功能障碍的新治疗策略

• 批准号: 10087935
• 负责人: Andrew J.W. Huang
• 金额: $ 18.98万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10087935
• 关键词: Adult; Affect; Affinity; Animal Model; Animals; Atrophic; Benchmarking; Blindness; Cancer Patient; Cell Proliferation; Clinical; Clinical Management; Clinical assessments; Communities; Desiccation; Disease; Dose; Doxycycline; Dry Eye Syndromes; Duct (organ) structure; Eye; Eye Injuries; Eyelid structure; FDA approved; FGF10 gene; FGF7 gene; FGFR1 gene; FGFR2 gene; Fibroblast Growth Factor; Fibroblast Growth Factor Receptor 2; Fibroblast Growth Factor Receptors; Film; Frequencies; Gene Deletion; Gland; Hematologic Neoplasms; High Prevalence; Homeostasis; Human; Injections; Lead; Life; Ligands; Lipids; Liquid substance; Maintenance; Modeling; Monitor; Mus; Mutant Strains Mice; Natural regeneration; Obstruction; Oils; Oral Administration; Outcome; Pathogenesis; Pathogenicity; Physiologic pulse; Play; Process; Production; Productivity; Publishing; Quality of life; Receptor Signaling; Regenerative capacity; Reporting; Reproducibility; Research; Residual state; Risk; Role; Second Primary Cancers; Severities; Signal Pathway; Signal Transduction; System; Therapeutic; Therapeutic Intervention; Tissues; Topical application; Toxic effect; Visual impairment; age related; analog; conditional knockout; dosage; effective therapy; evaporation; intraperitoneal; keratinocyte growth factor; meibomian gland; meibomian gland dysfunction; mouse model; novel therapeutic intervention; ocular surface; oral mucositis; palliative; preclinical study; prevent; receptor; repaired; stem cells; tissue injury; tissue regeneration; tissue repair; tool

PROJECT ABSTRACT Dry eye disease (DED) is a multifactorial disease characterized by desiccation of the ocular surface, potentially leading to permanent injury of the ocular surface and visual impairment. The most common cause of evaporative DED is meibomian gland dysfunction (MGD) which is characterized by glandular atrophy and/or ductal obstruction. Despite the high prevalence of MGD in DED, very little is known about its pathogenic mechanisms, and no targeted and effective treatments exist to restore meibomian gland (MG) function. Current treatments are mostly palliative and unsatisfactory, since they simply aim at symptomatic relief of DED, not at the underlying cause of MGD. A major obstacle in developing new strategies for effective treatment of MGD is the lack of an animal model that recapitulates MGD in humans. A unique mouse model of MGD has been created in which fibroblast growth factor receptor 2 (Fgfr2) is depleted upon induction by doxycycline (Dox). An advantage of this mouse model (referred as Fgfr2CKO ) is that gene deletion can be induced at various stages of the animal’s life and the extent of gene deletion (and thus the extent of MG degeneration and capacity of tissue regeneration) can be modulated by the dosage, or frequency, of doxycycline (Dox) induction treatment. This capability provides a reproducible mouse model of MGD showing strong promise as a model of MGD in humans. In this application, the preliminary studies in the Fgfr2CKO mice support the hypothesis that the FGFR2-signaling pathway plays a critical role not only for MG homeostasis but also in glandular regeneration in adult mice. Therefore, it is plausible that FGF ligand that can act on the FGFR2-signaling pathways can prevent glandular atrophy and promote tissue regeneration, thus serving as MGD-specific therapeutics to treat evaporative DED. The first specific aim of this application is to perform clinical assessment and histopathological analysis of induced MG atrophy and spontaneous regeneration in Fgfr2CKO mice. The outcome will provide the critical benchmarks for Aim 2. The second specific aim is to assess the efficacy of targeting FGFR2 activity by FGF7 as a novel therapeutic strategy for MGD. These preclinical studies in this new mouse model not only will identify potential therapeutic strategies for restoring MG function but also will expand understanding of the pathogenesis of MGD in DED. More importantly, the proposed therapeutic strategy of targeting FGF-signaling pathways has never been explored and may revolutionize the clinical management of MGD.

项目摘要

项目成果

Spontaneous acinar and ductal regrowth after meibomian gland atrophy induced by deletion of FGFR2 in a mouse model.

• DOI: 10.1016/j.jtos.2021.11.005
• 发表时间: 2022-10
• 期刊: OCULAR SURFACE
• 影响因子: 6.4
• 作者: Yang, Xiaowei;Zhong, Xingwu;Huang, Andrew J. W.;Reneker, Lixing W.
• 通讯作者: Reneker, Lixing W.