Protease regulation of extracellular networks

描述（由申请人提供）：该提案将研究ADAMTS10对细胞外网络的调控，ADAMTS10是一种分泌金属蛋白酶，在隐性weil - marchesani综合征（WMS）中发生突变，WMS是一种罕见的遗传性结缔组织疾病。尽管罕见，但WMS具有相当大的生物医学意义，因为其临床表现与马凡氏综合征（MFS）相反，后者是一种更常见的由纤维蛋白1突变引起的疾病。与MFS相比，WMS的特点是身材矮小、指短、皮肤厚、关节僵硬和主动脉狭窄，但与MFS一样，存在晶状体脱位。显性WMS在临床上与隐性WMS难以区分，但它是由纤颤蛋白1突变引起的，这为MFS提供了很强的遗传联系。与fibrin -1一样，初步研究显示ADAMTS10基因在骨骼、手足间质、肺、皮肤、主要血管和心脏瓣膜中表达旺盛，表明其在结缔组织调节中具有广泛作用。我们发现ADAMTS10在体外特异性和高亲和力地结合纤原蛋白-1，并在原位定位于微原纤维。对AdamtslO缺失小鼠的初步研究已经确定了骨骼和肺部的一种表型，与原纤维蛋白缺乏小鼠模型形成对比。这种遗传关联和初步研究使我们假设ADAMTS10和原纤维蛋白- 1在结缔组织调节网络中有联系。为了明确ADAMTS10的生理作用并更好地理解这一调控网络，本项目要求资助两个特定目标：确定AdamtslO失活对小鼠和细胞的影响，并研究部分或全部AdamtslO缺乏是否会影响原纤维蛋白缺乏的小鼠模型。2. 明确ADAMTS10与纤原蛋白遗传关系的机制基础，并确定ADAMTS10在纤原蛋白网络中的作用。与公共卫生相关：该建议为解决Weill-Marchesani综合征的机制提供了机会，并获得了马凡综合征的新视角。了解ADAMTS10如何与原纤维蛋白网络整合可能对马凡综合征的疾病改变具有长期潜力。

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.