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

 描述（由申请人提供）：缺水性干眼是系统性自身免疫性疾病（如干燥综合征）最常见和最令人衰弱的临床表现之一。众所周知，慢性炎症是干眼病的主要驱动力，然而，疾病发生和进展的因果机制尚不清楚。因此，干眼没有治愈方法，患者的治疗选择很少。在自身免疫性疾病如SS中，缺水性干眼的一个长期被忽视的组成部分是连接感觉组织与分泌腺的角膜神经的复杂反射网络的破坏。这种神经网络的完整性对于维持健康的眼表至关重要，并且越来越多的证据表明神经支配本身是炎症的负调节剂。在本申请中，我们将使用干燥综合征的小鼠模型来定义导致干眼角膜和泪腺去神经支配的细胞过程，以及确定干燥综合征患者恢复神经支配和逆转眼表损伤的机制。我们假设慢性T细胞介导的炎症通过抑制角膜和泪腺中神经的上皮维持来改变神经支配，导致组织完整性丧失和泪液分泌减少，从而使眼表疾病和水性泪液缺乏持续存在。为了验证这一假设，我们将：1）定义干眼发展期间角膜、泪腺和相关神经的去神经支配和相应病理变化的时间;和2）确定T细胞介导的炎症改变角膜和泪腺的神经支配的机制。为了实现这些目标，我们将采用体内和体外研究的组合，以及转录谱，在一个良好的表征小鼠模型的干燥综合征。这里的结果将定义眼器官神经支配的调节剂，确定疾病进展的潜在生物标志物，并揭示逆转干眼病的新再生策略。

 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.