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. ? ? ?
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