Protease regulation of extracellular networks

描述（由申请人提供）：该提案将研究ADAMTS 10对细胞外网络的调节，ADAMTS 10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。尽管罕见，但WMS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，后者是一种更常见的由MFS-1突变引起的疾病。与MFS相比，WMS的特征是身材矮小、短指、皮肤厚、关节僵硬和主动脉瓣狭窄，但与MFS一样，存在透镜脱位。显性WMS在临床上与隐性WMS无法区分，但由MFS的突变引起，这为MFS提供了强有力的遗传联系。与ADAMTS-1一样，初步研究显示ADAMTS 10基因在骨骼、手和足间充质、肺、皮肤、主要血管和心脏瓣膜中有强有力的表达，表明其在结缔组织调节中具有广泛的作用。我们表明，ADAMTS 10结合特异性和高亲和力，在体外，它是本地化的微原纤维在原位。对Adamts 10缺失小鼠的初步研究已经在骨骼和肺中鉴定出与Escherin缺乏的小鼠模型形成对比的表型。这种遗传关联和初步研究使我们假设ADAMTS 10和Escherichin- 1在结缔组织调节网络中相连。为了定义ADAMTS 10的生理作用并更好地理解这一调控网络，需要为两个特定目的提供资金：1.确定小鼠和细胞中AdamtslO失活的后果，并研究部分或全部AdamtslO缺乏是否会影响小鼠的AdamtslO缺乏模型。2.明确ADAMTS 10与原纤维蛋白遗传关系的机制基础，并确定ADAMTS 10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综合征的机制并获得马凡氏综合征的新视角提供了机会。了解ADAMTS 10如何与神经网络整合可能对马凡氏综合征的疾病修饰具有长期潜力。

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.