Structure and Function of Ocular Lacritin

我们完全改写的应用程序将泪液/角膜轴作为眼睛健康的基本调节因素。我们寻求对泪腺泡细胞分泌控制如何管理及其下游后果的全球理解。基础和反射性泪液分泌的调节是复杂的，在很大程度上是未知的和可逆的；并在干眼综合征的神秘病因中发挥作用，对于干眼症来说，基础和反射性泪液分泌能力通常是不同的不足。主要泪腺的“基底性”和“反射性”撕裂(描述眼表输出的术语)是腺泡细胞的“构成”、“构成样”、“次要调节”(基础)和“主要调节”(反射)分泌途径--每一种分泌途径在腮腺等其他外分泌器官中的大部分都具有特定的特征。假设可能存在受体介导的自分泌反馈环(S)，其中一条分泌途径释放的分泌产物(S)增强或减少另一条分泌途径的分泌，这一潜在的敏感安排为干眼患者泪液分泌不足的研究提供了一个新的框架。最近我们发现了lacritin，一种泪腺泡细胞基础分泌的自分泌增强剂(Sanghi等人，J.Mol。比奥尔。‘01；封面问题)。Lacritin高度保守，并通过主要的调节途径从泪腺泡细胞释放。它以剂量依赖的方式促进基础泪液分泌，并迅速激活低幅度钙信号和酪氨酸磷酸化。Lacritin还促进下游导管细胞的增殖和角膜上皮细胞的钙信号转导。估计细胞结合亲和力为0.03-0.07 NM(相对于NGF[0.01-1 NM]，EGF[0.2 NM]，PDGF[0.4-0]。7海里])。表达研究表明，lacritin基因是所描述的泪腺特异性最强的基因之一。我们的工作假设是，Lacritin的释放以一种G蛋白偶联受体依赖的方式刺激次要调节途径，而导管和角膜上皮细胞中相同受体的连接调节细胞周转。因此，我们的具体目标是：(1)鉴定和表征Lacritin如何与靶细胞表面接触；(2)阐明Lacritin依赖的分泌途径的身份、激活机制和意义；(3)阐明Lacritin在下游导管和眼表的作用。

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.