The specific goal of this application is to identify and characterize the molecular events leading to elastic fiber alterations and calcification in pseudoxanthoma elasticum (PXE) as a pertinent disease model to better understand the dynamics governing the super-assembly and homeostasis of elastic fibers. These are large, complex molecules that provide mechanical properties to elastic tissues and regulate cell fate in many developing tissues. These fibers are essential for the development of life but how they are assembled and maintained is not fully understood. Pseudoxanthoma elasticum (PXE) is a heritable disease characterized by elastic fiber fragmentation and calcification. PXE was long thought to be a prototypic connective tissue disease but the PXE phenotype was unexpectedly linked to a gene (ABCC6) apparently unrelated to elastic fibers. We have obtained preliminary results showing that circulating factors from PXE patient sera altered elastic fibers formation in vitro. This data suggested that PXE is a metabolic disorder with secondary extracellular matrix remodeling and that circulating factors might either participate in or exacerbate the development of the disease phenotype. Hence, we hypothesize that abnormal circulating factor(s) arise in the blood as a secondary consequence of ABCC6 failure to export its substrate(s);these PXE factor(s) then percolate from the circulation into the connective tissue and either preclude the initial deposition of elastic fibers or promote structural alterations that ultimately result in their calcification. To test this hypothesis, we propose to undertake two specific aims corresponding to (i) the molecular characterization of elastic fiber defects induced by the presence of serum from PXE patients in culture of dermal fibroblasts (ii) the identification of the serum factor(s) responsible for the these defects. We expect that our proposed experiments will lead to the identification of factor(s) interfering with elastic fiber and the possible development of therapeutic measures alleviating the symptoms of PXE. We also anticipate from our studies a new level of understanding of elastic fiber formation and aging in vascular tissues. PUBLIC HEALTH RELEVANCE: Elastic fibers are large, complex molecules that are important for life by providing specific mechanical properties to elastic tissues. To understand how elastic fibers are maintained over time, we are exploring the pathologic mechanism underlying pseudoxanthoma elasticum, a heritable disease, characterized by progressive elastic fiber fragmentation and calcification.

R21HL087289

2009-07-01

2012-06-30