Molecular Basis of Myocilin Function in the Human Eye

描述（申请人提供）：涉及的第一种分子组分 开角型青光眼的发病机理已经被确定。突变导致 一些青光眼患者的开角型青光眼基因GLC 1A位于 1号染色体编码一种叫做肌球蛋白的蛋白质。Myocilin是一本小说 一种在几种眼组织中发现的功能未知的蛋白质，包括 小梁网，开角型青光眼的可能病理部位。上 在亚细胞水平，myociin定位于小梁的囊泡室， 网状细胞，涉及受影响的囊泡运输和/或分泌 开角型青光眼的发病机制myocilin蛋白原的计算机分析 序列表明与SNARE [可溶性N-乙基马来酰亚胺]具有显著的同源性 敏感融合蛋白（NSF）附着蛋白（SNAP）受体]和 嗅觉介导蛋白家族，这两个蛋白都定位于并在嗅觉系统中发挥作用。 细胞的分泌途径。此外，本报告中提供的初步数据 提示：1）myocilin在形成和融合过程中都起作用 小梁网（HTM）细胞中的分泌型囊泡和2） myocilin相关囊泡参与新生的 两种不同上皮细胞模型中的细胞-细胞连接。因此， 这项拨款提案的目标是确定myocilin在这一过程中的作用 小梁网细胞中新生细胞-细胞连接组装和 在此过程中，myocilin突变的功能后果。为此目的， myocilin与已知参与 新生细胞-细胞连接将在HTM细胞中进行。二是 肌球蛋白对HTM细胞中新生细胞-细胞连接的调节靶向 将被研究。最后，肌球蛋白突变的功能后果 将使用HTM细胞作为模型来监测（在人类中引起的疾病）。 这些研究的目的是检查分子途径，其中肌球蛋白 在HTM细胞中发挥作用。这些知识将有助于我们理解 为青光眼的治疗提供新的靶点。 治疗青光眼的方法

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.