Defining the role of immune-neuronal crosstalk in dry eye disease

 描述(申请人提供)：缺水干眼是全身性自身免疫性疾病最常见和最虚弱的临床表现之一，如干燥综合征。众所周知，慢性炎症是干眼病的主要驱动力，然而，疾病发生和发展的原因机制尚不清楚。因此，干眼症无法治愈，患者的治疗选择也很少。在SS等自身免疫性疾病中，缺水干眼的一个长期被忽视的成分是连接感觉组织和分泌腺的复杂的角膜神经反射网络的破坏。这种神经网络的完整性对于维持健康的眼表至关重要，越来越多的证据表明，神经支配本身是炎症的负面调节因素。在本应用中，我们将使用Sjögren综合征的小鼠模型来定义导致干眼症患者角膜和泪腺失神经的细胞过程，并确定恢复神经支配和逆转Sjögren综合征患者眼表损害的机制。我们假设，慢性T细胞介导的炎症通过抑制角膜和泪腺神经的上皮维持而改变神经，导致组织完整性的丧失和泪液分泌的减少，从而使眼表疾病和泪液缺乏永久化。为了验证这一假设，我们将：1)确定干眼发育过程中角膜、泪腺和相关神经失神经的时间和相应的病理变化；2)确定T细胞介导的炎症改变角膜和泪腺神经支配的机制。为了实现这些目标，我们将采用体内和体外研究相结合的方法，以及在具有良好特征的Sjögren综合征小鼠模型中进行转录图谱分析。这些结果将定义眼器官神经支配的调节器，识别疾病进展的潜在生物标记物，并揭示逆转干眼病的新的再生策略。

 DESCRIPTION (provided by applicant): Aqueous-deficient dry eye is among the most common and debilitating clinical manifestations of systemic autoimmune diseases such as Sjögren's syndrome. It is well established that chronic inflammation represents the predominant driving force in dry eye disease, however, the causal mechanisms underlying disease initiation and progression are unclear. As such, there is no cure for dry eye and few treatment options are available for sufferers. A long overlooked component of aqueous-deficient dry eye in autoimmune diseases like SS, is disruption of the complex reflex network of corneal nerves that connect the sensory tissues with the secretory glands. The integrity of this neural network is essential for maintaining a healthy ocular surface and there is growing evidence that innervation itself is a negative modulator of inflammation. In this application we will use a mouse model of Sjögren's syndrome to define the cellular processes that lead to denervation of the cornea and lacrimal gland in dry eye, as well as identify mechanisms to restore innervation and reverse ocular surface damage in Sjögren's syndrome patients. We hypothesize that chronic, T cell-mediated inflammation alters innervation by inhibiting epithelial maintenance of nerves in the cornea and lacrimal gland, resulting in loss of tissue integrity and reduced tear secretion that perpetuate ocular surface disease and aqueous tear deficiency. To test this hypothesis we will: 1) Define the timing of denervation and corresponding pathological changes in the cornea, lacrimal gland and associated nerves during dry eye development; and 2) Determine the mechanisms by which T cell-mediated inflammation alters innervation of the cornea and lacrimal glands. To achieve these aims we will employ a combination of in vivo and ex vivo studies, as well as transcriptional profiling, in a well-characterized mouse model of Sjögren's syndrome. Outcomes here will define modulators of ocular organ innervation, identify potential biomarkers of disease progression, and reveal novel regenerative strategies for reversing dry eye disease.