Proteinase Inhbitors & Crystallin Fragments in Cataract

在老化过程中，增加比例的总透镜蛋白质变得不溶于水（W1），或者由于聚集 和/或交联。这些物质进一步交联成共价多聚体被认为会导致不透明 在年龄相关性（老年性）白内障的发展过程中， 在文献中被描述为交联机制的致病因素，但它们的相对作用尚不清楚。 由于老年性白内障的发展是一个缓慢的过程，有时需要数年，很少有具体的修改 可能会作为加速交联机制和导致透镜不透明的粘合剂。我们的结果显示 修饰的堆叠片段在晶状体蛋白交联过程中起积极作用。要理解这样一个角色， 晶体蛋白片段，必须确定其来源，翻译后修饰和交联机制 in order订购to implicate暗示them as a causative致病factor因素.基于我们的结果，我们假设bA3/A1-晶体蛋白 含有蛋白酶活性，但由于酶活性需要活化，因此活性在体内受到调节， 活性酶被α-晶状体蛋白抑制。bA3/A1-晶体蛋白酶蛋白水解a-、B-和g-晶体蛋白， 晶体蛋白片段经历后结晶修饰，导致它们本身交联， phakinin和filensin（透镜珠状丝蛋白）形成共价多聚体。这些共价多聚体导致 透镜不透明度。为了验证上述假设，本文拟研究的问题主要集中在以下三个方面 问题：（A）bA3/p53的Arg键水解蛋白酶活性激活的分子机制是什么？ A1-晶体蛋白？(B)体内B A3/A1-晶体蛋白酶活性是如何调节的？(C)什么是共价交叉- 连接机制的post-actionallymodified晶体蛋白片段本身，并与phakinin和filensin？ 上述研究将提供一个答案的核心问题，如何不透明发展过程中与年龄有关的 白内障发展由于这些研究将使用人类晶状体，因此这些发现将与 阐明了B A3/A1晶体的作用!在晶体蛋白的蛋白水解中的蛋白酶，它们在体内的调节， 特别是堆叠片段本身以及与phakinin和filensin的交联机制。

During aging, an increasing proportion of total lens proteins becomes water insoluble (Wl), either due to aggregation and/or cross-linking. A further cross-linking of these species into covalent multimers is believed to cause opacity during age-related(senile) cataract development.A variety of post-translational modifications of crystallins are described in the literature as causativefactors for cross-linking mechanism, but their relative roles remain unclear. Because the senile cataract development is a slow process and sometimes takes years, few specific modifications might act as triggersto acceleratethe cross-linking mechanism and cause lens opacity. Our results show that modified crystallinfragments play an active role in the crystallin cross-linking process. To understand such a role of crystallin fragments,one must determine their origin, post-translational modifications and cross-linking mechanism in order to implicatethem as a causativefactor. Based on our results, we have hypothesized that bA3/A1 -crystallin contains proteinaseactivity, but the activity is regulated in vivo because the enzyme activity needed activation, and the active enzyme is inhibited by a-crystallin. The bA3/A1-crystallin proteinase proteolyses a-, b- and g-crystallins, and the crystallin fragments undergo post-translationalmodifications, leading to their cross-linking per se and with phakinin and filensin (lens beaded filament proteins) to form covalent multimers. These covalent multimers cause lens opacity. To test the above hypothesis,the proposed studies will be focused to answer the following three major questions: (A) What is the molecular mechanism of activation of an Arg-bond hydrolyzing proteinase activity of bA3/ A1-crystallin? (B) How is the b A3/A1-crystaltin proteinase activity regulated in vivo? (C) What is the covalent cross- linking mechanismof post-translationallymodified crystallin fragments per se and with phakinin and filensin? The above studieswill provide an answerto the central question of how opacity develops during age-related cataract development. Because human lenses will be used in these studies, the findings will be relevant in elucidating the role of b A3/A1-crystal!in proteinase in the proteolysis of crystallins, their regulation in vivo, and in particular the mechanismof cross-linkingof crystallinfragments per se and with phakinin and filensin.