Molecular Basis of Myocilin Function in the Human Eye

描述(申请人提供)：涉及的第一个分子组分 开角型青光眼的发病机制已明确。突变导致 青光眼中的一些人定位于开角型青光眼基因GLC1AOn 1号染色体编码一种名为myoclin的蛋白质。麦考林是一部小说 一种未知功能的蛋白质，存在于几种眼睛组织中，包括 小梁网，开角型青光眼可能的病理部位。vt.在.上 在亚细胞水平，myociin定位于小梁的囊泡室 网络细胞，涉及受影响的囊泡运输和/或分泌 开角型青光眼的治疗途径。霉菌素原生性的计算机分析 序列表明与SNARE[可溶性N-乙基马来酰亚胺]有显著同源性 敏感融合蛋白(NSF)附着蛋白(SNAP)受体]和 嗅觉调节蛋白家族，这两个家族都定位于并在其中发挥作用 细胞的分泌途径。此外，这份报告中提供的初步数据 建议指出：1)肌球蛋白在形成和融合过程中都起作用 小梁网(HTM)细胞分泌型小泡的数量和2) 肌球蛋白相关囊泡参与新生细胞的调控组装 两种不同的上皮细胞模型中的细胞-细胞连接。因此，总体上， 这项拨款提案的目标是确定麦考林在这一过程中的作用。 小梁细胞中的新生细胞-细胞连接组装和 肌红素突变在这一过程中的功能后果。为此， 霉菌素与已知参与蛋白的共定位研究 新生的细胞-细胞连接将在HTM细胞中进行。第二， 霉菌素对HTM细胞新生细胞-细胞连接的调控靶向性 将会被研究。最后，肌球蛋白基因突变的功能后果 (人类致病)将使用HTM细胞作为模型进行监测。 这些研究旨在研究肌红素的分子途径。 在HTM细胞中发挥作用。这一知识将有助于我们理解 从分子水平研究青光眼，为青光眼治疗提供新的靶点 青光眼患者的治疗。

DESCRIPTION (provided by applicant): The first molecular component involved in the pathogenesis of open-angle glaucoma has been identified. Mutations causing glaucoma in some are located to an open-angle glaucoma gene, GLC1A, on chromosome 1 that codes for a protein called myocilin. Myocilin is a novel protein of unknown function that is found in several eye tissues, including the trabecular meshwork, the likely site of pathology in open-angle glaucoma. On a subcellular level, myociin localizes to the vesicular compartment of trabecular meshwork cells, implicating vesicular traffic and/or secretion as affected pathways in open-angle glaucoma. Computer analyses of myocilin's primary sequence indicate significant homology to the SNARE [soluble N-ethylmaleimide sensitive fusion protein (NSF) attachment protein (SNAP) receptor] and Olfactomedin protein families, both of which localize to and function in the secretory pathway of cells. Moreover, preliminary data presented in this proposal indicate that 1) myocilin functions in both the formation and fusion of secretory-type vesicles in trabecular meshwork (HTM) cells and 2) myocilin-associated vesicles participate in the regulated assembly of nascent cell-cell junctions in two different epithelial cell models. Thus, the overall goal of this grant proposal is to determine the role of myocilin in the process of nascent cell-cell junction assembly in trabecular meshwork cells and the functional consequence of mutations in myocilin on this process. To this end, colocalization studies of myocilin with proteins known to participate in nascent cell-cell junctions will be performed in HTM cells. Second, the regulated targeting of myocilin to nascent cell-cell junctions in HTM cells will be studied. Finally, the functional consequence of mutations in myocilin (disease causing in humans) will be monitored using HTM cells as a model. These studies are designed to examine the molecular pathway in which myocilin functions in HTM cells. This knowledge will contribute to our understanding of glaucoma at the molecular level and provide new therapeutic targets for the treatment of those who are afflicted with glaucoma.