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

项目摘要 干眼症（DED）是一种多因素疾病，其特征在于眼表干燥， 导致眼表面的永久性损伤和视力损害。的最常见原因 蒸发性DED是睑板腺功能障碍（MGD），其特征在于腺体萎缩和/或 导管阻塞尽管MGD在DED中的患病率很高，但对其致病性知之甚少 目前还没有靶向和有效的治疗方法来恢复睑板腺（MG）功能。 目前的治疗大多是姑息性的和不令人满意的，因为它们只是旨在缓解DED的症状， 而不是MGD的根本原因制定有效治疗糖尿病的新战略的一个主要障碍 MGD缺乏在人类中重现MGD的动物模型。一种独特的MGD小鼠模型， 其中成纤维细胞生长因子受体2（Fgfr 2）在多西环素诱导后被耗尽 （Dox）.该小鼠模型（称为Fgfr 2CKO）的优点是基因缺失可以在 动物生命的各个阶段和基因缺失的程度（以及因此MG变性的程度和 组织再生能力）可以通过多西环素（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复的MGD小鼠模型，显示出作为模型的强大前景 MGD在人类在本申请中，在Fgfr 2CKO小鼠中的初步研究支持以下假设： FGFR 2信号通路不仅对MG体内平衡起关键作用， 成年小鼠的再生。因此，可能的是，可以作用于FGFR 2信号传导的FGF配体 途径可以防止腺体萎缩，促进组织再生，从而作为MGD特异性 用于治疗蒸发性DED的治疗剂。本申请的第一个具体目的是进行临床试验。 Fgfr 2CKO中诱导的MG萎缩和自发再生的评估和组织病理学分析 小鼠其结果将为目标2提供关键基准。第二个具体目标是评估 通过FGF 7靶向FGFR 2活性作为MGD的新治疗策略的功效。这些临床前 在这种新的小鼠模型中的研究不仅将确定恢复MG功能的潜在治疗策略， 而且将扩大对DED中MGD发病机制的理解。更重要的是， 靶向FGF信号通路的治疗策略从未被探索过，并且可能会彻底改变 MGD的临床管理。

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.