Structure and Function of Ocular Lacritin

我们完全重写的申请地址泪/角膜轴作为眼部健康的基本调节。我们寻求泪腺泡细胞分泌控制是如何控制和下游后果的全球理解。基底和反射性泪液分泌的调节是复杂的，大部分未被探索和可逆的；干眼综合征的基础和反射性流泪能力往往是差异不足的。主要泪腺的“基础”和“反射”流泪（描述眼表输出的术语）是腺泡细胞的“构成”、“类似构成”、“次要调节”（基础）和“主要调节”（反射）分泌途径——每一个都有其他外分泌器官（如腮腺）的大部分特征。假设可能存在一种受体介导的自分泌反馈回路，其中一种分泌途径释放的分泌产物会增强或减少另一种分泌途径的分泌，这一潜在的敏感安排为研究干眼症的泪液分泌不足提供了一个新的框架。近年来，我们发现了催泪素，一种能促进泪腺细胞基底分泌的自分泌因子（Sanghi et al .， J. Mol. Biol.）。' 01;覆盖问题)。泪素是高度保守的，并通过主要调控途径从泪腺细胞中释放出来。它以剂量依赖的方式增强基底泪液分泌，并迅速激活低振幅钙信号和酪氨酸磷酸化。泪泌素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 nM]）。7海里)。表达研究表明，泪素基因是最具泪腺特异性的基因之一。我们的工作假设是，泪泌素的释放以G蛋白偶联受体依赖的方式刺激次要调节通路，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)识别和表征泪泌素与靶细胞表面的接触方式；(2)阐明泪泌素依赖分泌途径的身份、激活机制和意义；(3)阐明泪泌素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.