Protease regulation of extracellular networks

描述(申请人提供)：该提案将研究ADAMTS10对细胞外网络的调节，ADAMTS10是一种在隐性Weill-Marchesani综合征(WMS)中突变的分泌型金属蛋白酶，WMS是一种罕见的遗传性结缔组织疾病。尽管WMS很罕见，但它具有相当大的生物医学意义，因为它的临床表现与马凡综合征(MFS)相反，马凡综合征是一种更常见的疾病，由纤维蛋白-1突变引起。与MFS相比，WMS的特点是身材矮小、指趾短、皮肤厚、关节僵硬和主动脉狭窄，但与MFS一样，也有晶状体脱位。显性WMS与隐性WMS在临床上难以区分，但由原纤维蛋白-1基因突变引起，这与MFS有很强的遗传联系。与纤维蛋白-1一样，初步研究表明ADAMTS10基因在骨骼、手足间充质、肺、皮肤、主要血管和心脏瓣膜中表达旺盛，表明在结缔组织调节中具有广泛的作用。我们发现ADAMTS10在体外与纤维蛋白-1特异性结合并具有高亲和力，并在原位定位于微纤维。对AdamtslO基因缺失小鼠的初步研究发现，骨骼和肺中的一种表型与纤维素缺乏症小鼠模型形成了鲜明对比。这种遗传关联和初步研究使我们假设ADAMTS10和纤维蛋白-1在结缔组织调控网络中是相连的。为了确定ADAMTS10的生理作用并更好地理解这个调控网络，需要为两个特定目标申请资金：1.确定AdamtslO失活在小鼠和细胞中的后果，并调查AdamtslO部分或全部缺乏是否会影响纤维蛋白缺乏的小鼠模型。2.明确ADAMTS10与纤维蛋白遗传关系的机制基础，确定ADAMTS10在纤维蛋白网络中的作用。与公共卫生的相关性：该提案为解决Weill-Marchesani综合征的机制提供了机会，并获得了对Marfan综合征的新视角。对ADAMTS10如何与纤维蛋白网络整合的了解可能会对马凡综合征的疾病改进具有长期的潜力。

DESCRIPTION (provided by applicant): The proposal will investigate regulation of extracellular networks by ADAMTS10, a secreted metalloprotease mutated in recessive Weill-Marchesani syndrome (WMS), a rare inherited connective tissue disorder. Despite its rarity, WMS is of considerable biomedical significance because its clinical picture is the opposite of Marfan syndrome (MFS), a more common disorder caused by fibrillin-1 mutations. In contrast to MFS, WMS is characterized by short stature, brachydactyly, thick skin, stiff joints and aortic stenosis but like MFS, there is dislocation of the lens. Dominant WMS is clinically indistinguishable from recessive WMS, but is caused by mutations in fibrillin-1, providing a strong genetic link to MFS. Like fibrillin-1, preliminary studies show robust ADAMTS10 gene expression in the skeleton, hand and foot mesenchyme, lung, skin, major blood vessels and heart valves, suggesting a broad role in connective tissue regulation. We show that ADAMTS10 binds specifically and with high affinity to fibrillin-1 in vitro and that it is localized to microfibrils in situ. Preliminary studies of AdamtslO null mice have identified a phenotype in the skeleton and lungs that contrasts with mouse models of fibrillin deficiency. This genetic association and the preliminary studies have led us to hypothesize that ADAMTS10 and fibrillin- 1 are linked in a connective tissue regulatory network. To define the physiological role of ADAMTS10 and better understand this regulatory network, funding is requested for two Specific Aims: 1. To determine the consequences of AdamtslO inactivation in mice and cells and to investigate whether partial or total AdamtslO deficiency will influence mouse models of fibrillin deficiency. 2. To define the mechanistic basis for the genetic relationship of ADAMTS10 with fibrillins and to determine the role of ADAMTS10 in fibrillin networks. Relevance to public health: The proposal offers an opportunity to solve the mechanism of Weill-Marchesani syndrome and obtain a novel perspective on Marfan syndrome. An understanding of how ADAMTS10 integrates with fibrillin networks may have long-term potential for disease modification in Marfan syndrome.