Structure and Function of Ocular Lacritin

我们完全重写的应用程序将泪腺/角膜轴作为眼睛健康的基本调节器。 我们寻求一个全球性的了解泪腺泡细胞分泌控制是如何管理和下游的后果。基础和反射性泪液分泌的调节是复杂的，在很大程度上是未探索的和可逆的;并且在干眼综合征的神秘病因学中起作用，干眼综合征的基础和反射性泪液分泌能力通常是差异性缺乏的。 在主泪腺“基底”和“反射”流泪（描述眼表面输出的术语）的基础上，是腺泡细胞的“组成型”、“组成型样”、“次要调节型”（基底）以及“主要调节型”（反射）分泌途径-每种途径都具有在其他外分泌器官（如腮腺）中大部分定义的特定特征。 假设可能存在受体介导的自分泌反馈环，其中从一个分泌途径释放的分泌产物增强或减少从另一个途径的分泌，这是一种潜在的敏感安排，为研究干眼症中的泪液分泌不足提供了新的框架。 最近，我们发现了催泪蛋白，一种泪腺泡细胞基础分泌的自分泌增强剂（Sanghi等人，J. Mol. Biol. '01;封面问题）。 泪腺素是一种高度保守的蛋白质，通过主要的调控途径从泪腺泡细胞中释放。 它以剂量依赖性方式增强基础泪液分泌，并快速激活低幅度钙信号传导和酪氨酸磷酸化。 Lacritin还促进下游导管细胞的增殖和角膜上皮细胞的钙信号传导。 估计的细胞结合亲和力为0.03 - 0.07 nM（相对于NGF [0.01 - 1 nM]、EGF [0.2 nM]、PDGF [0.4 - 0. 7nM]）。 表达研究表明，催泪素基因是一个最泪腺特异性的描述。 我们的工作假设是，催乳素的释放以G蛋白偶联受体依赖性方式刺激次要调节途径，并且导管和角膜上皮细胞中相同受体的连接调节细胞更新。因此，我们的具体目标是：（1）鉴定和表征催乳素如何接触靶细胞表面，（2）阐明催乳素依赖性分泌途径的身份，其激活机制和意义，以及（3）阐明催乳素的下游导管和眼表作用。

Our entirely rewritten application addresses the lacrimal/corneal axis as a fundamental regulator of ocular health. We seek a global understanding of how lacrimal acinar cell secretory control is governed and downstream consequences. Modulation of basal and reflex tear secretion is complex, largely unexplored and reversible; and plays into the enigmatic etiology of Dry Eye syndromes for which basal and reflex tearing capacity is often differentially deficient. Underlying main lacrimal gland 'basal' and 'reflex' tearing (terms that describe output at the ocular surface) are the acinar cell 'constitutive', 'constitutive-like', 'minor regulated' (basal) as well as 'major regulated' (reflex) secretory pathways - each with particular characteristics defined for the most part in other exocrine organs such as the parotid. Hypothetically possible is a receptor-mediated autocrine feedback loop(s) in which secretory product(s) released from one secretory pathway enhance or diminish secretion from another pathway, a potentially sensitive arrangement offering a novel framework for studying lacrimal hyposecretion in Dry Eye. Recently we discovered lacritin, an autocrine enhancer of lacrimal acinar cell basal secretion (Sanghi et al, J. Mol. Biol. '01; cover issue). Lacritin is highly conserved and released from lacrimal acinar cells by the major regulated pathway. It enhances basal tear secretion in a dose dependent manner, and rapidly activates both low amplitude calcium signaling and tyrosine phosphorylation. Lacritin also promotes the proliferation of downstream ductal cells and calcium signaling by corneal epithelial cells. Estimated cell binding affinity is 0.03 - 0.07 nM (versus NGF [0.01 - 1 nM], EGF [0.2 nM], PDGF [0.4 - 0. 7 nM]). Expression studies suggest that the lacritin gene is one of the most lacrimal gland-specific described. Our working hypothesis is that lacritin release stimulates the minor regulated pathway in a G -protein coupled receptor dependent manner, and that ligation of the same receptor in ductal and corneal epithelial cells regulates cell turnover. Our specific aims are therefore: (1) to identify and characterize how lacritin contacts target cell surfaces, (2) to clarify the identity of the lacritin-dependent secretory pathway, its mechanism of activation and significance, and (3) to elucidate lacritin's downstream ductal and ocular surface role.