MOLECULAR BASIS OF MYOCILIN FUNCTION IN THE HUMAN EYE

一种与开角型青光眼发病有关的分子成分已被确定。 一些导致高眼压和开角型青光眼的突变位于青光眼基因 在1号染色体的GLC1a基因座上，编码一种名为myoclin的蛋白质。不幸的是， 麦角菌素是未知的。几种眼部组织表达myocin，包括小梁网、 可能是开角型青光眼高眼压的病理部位。在亚细胞水平上，肌球蛋白 定位于小梁细胞的囊泡室，暗示囊泡交通和/或 分泌物在青光眼中的影响途径。本项目初期资助期的进展情况 其特征是肌球蛋白是一种胞浆蛋白，与一类细胞内小泡有关 小梁网细胞称为“外体”。因此，麦角菌素不是以传统的方式分泌，而是 离开小梁网络细胞，进入与外切体相关的细胞外腔。 本研究的总体目标是确定肌球蛋白在小梁网中的功能。 以及myocin的突变如何影响其细胞外外观。我们假设基因突变在 霉菌素干扰外切体的释放。为了验证这一假设，我们设计了两个 互补的特定目标：(I)确定Myocin与细胞内结合的机制 小梁细胞的膜(外切体)和(Ii)确定myocin突变体对 人眼小梁细胞释放外切体。

A molecular component involved in the pathogenesis of open-angle glaucoma has been identified. Mutations causing ocular hypertension and open-angle glaucoma in some are located to a glaucoma gene on a chromosome 1 locus, GLC1A, that codes for a protein called myocilin. Unfortunately the function of myocilin is unknown. Myocilin is expressed by several eye tissues, including the trabecular meshwork, the likely site of pathology for ocular hypertension in open-angle glaucoma. On a subcellular level, myocilin localizes to the vesicular compartment of trabecular meshwork cells, implicating vesicular traffic and/or secretion as affected pathways in glaucoma. Progress in the initial funding period of this project characterized myocilin as a cytosolic protein that associates with a class of intracellular vesicles in trabecular meshwork cells called "exosomes". Thus, myocilin is not secreted in a traditional manner, but exits trabecular meshwork cells and enters the extracellular compartment associated with exosomes. The overall goal of the present proposal is to determine the function of myocilin in trabecular meshwork cells and how mutations in myocilin impact its extracellular appearance. We hypothesize that mutations in myocilin interfere with delivery of exosomes for release. To test this hypothesis, we have designed two complimentary specific aims: (i) Identify the mechanism by which myocilin associates with intracellular membranes (exosomes) in trabecular meshwork cells and (ii) Determine effects of myocilin mutants on release of exosomes from human trabecular meshwork cells .