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

项目摘要 干眼病(DED)是一种以眼表面干燥为特征的多因素疾病，潜在地 导致眼表永久性损伤和视力损害。最常见的原因是 蒸发性DED是以腺体萎缩和/或腺体萎缩为特征的汗腺功能障碍(MGD) 导管阻塞。尽管在DED中MGD的发病率很高，但对其致病原因知之甚少。 目前尚无针对性有效的治疗方法来恢复眉板腺(MG)的功能。 目前的治疗大多是姑息性的，并不令人满意，因为它们只是针对DED的症状缓解， 而不是针对MGD的根本原因。制定新的有效治疗策略的主要障碍 MGD是指缺乏一种可以概括人类MGD的动物模型。一种独特的MGD小鼠模型 在多西环素诱导下，成纤维细胞生长因子受体2(FGFR2)被耗尽 (DOX)。这种小鼠模型(称为Fgfr2CKO)的一个优点是，可以在 动物生命的不同阶段和基因缺失的程度(因此MG的退化和 组织再生能力)可以由多西环素(Dox)诱导的剂量或频率来调节 治疗。这种能力提供了一种可重现的MGD小鼠模型，显示出作为模型的强大前景 MGD在人类中的作用。在这一应用中，对Fgfr2CKO小鼠的初步研究支持这样的假设 FGFR2信号通路不仅在MG动态平衡中起关键作用，而且在腺体中也起着关键作用 成年小鼠的再生。因此，可以认为作用于FGFR2-信号的成纤维细胞生长因子配体是可能的 途径可以防止腺体萎缩和促进组织再生，从而作为MGD特异性的 治疗蒸发性DED。此应用程序的第一个特定目标是执行临床 Fgfr2CKO诱导MG萎缩和自发再生的评价及组织病理学分析 老鼠。结果将为目标2提供关键基准。第二个具体目标是评估 Fgf7靶向FGFR2活性作为治疗MGD的新策略的有效性。这些临床前研究 对这种新的小鼠模型的研究不仅将确定恢复MG功能的潜在治疗策略 也将扩大对DED中MGD发病机制的认识。更重要的是，建议的 靶向成纤维细胞生长因子信号通路的治疗策略从未被探索过，可能会彻底改变 MGD的临床处理。

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.