Pseudoxanthoma elasticum: Elastic fibers alterations and characterization of seru

描述（由申请人提供）：本申请的具体目标是鉴定和表征导致弹性假黄瘤（PXE）中弹性纤维改变和钙化的分子事件，作为相关疾病模型，以更好地理解控制弹性纤维超组装和稳态的动力学。这些是大的复杂分子，为弹性组织提供机械特性，并调节许多发育组织中的细胞命运。这些纤维对生命的发展至关重要，但它们是如何组装和维持的还不完全清楚。弹性纤维性假黄瘤是一种以弹性纤维断裂和钙化为特征的遗传性疾病。PXE长期以来被认为是一种典型的结缔组织疾病，但PXE表型出乎意料地与一个明显与弹性纤维无关的基因（ABCC 6）有关。我们已经获得的初步结果表明，从PXE患者血清循环因子改变弹性纤维的形成在体外。这些数据表明，PXE是一种代谢紊乱与继发性细胞外基质重塑和循环因子可能参与或加剧疾病表型的发展。因此，我们假设血液中出现的异常循环因子是ABCC 6未能输出其底物的继发结果;这些PXE因子随后从循环中渗透到结缔组织中，并阻止弹性纤维的初始沉积或促进最终导致其钙化的结构改变。为了检验这一假设，我们提出了两个具体的目标，对应于（i）皮肤成纤维细胞培养物中存在的来自PXE患者的血清诱导的弹性纤维缺陷的分子表征（ii）负责这些缺陷的血清因子的鉴定。我们希望我们提出的实验将导致识别的因素（S）干扰弹性纤维和可能的发展的治疗措施，减轻症状的PXE。我们还期望从我们的研究中对血管组织中弹性纤维的形成和衰老有一个新的认识水平。公共卫生相关性：弹性纤维是大的、复杂的分子，其通过向弹性组织提供特定的机械特性而对生命很重要。为了了解弹性纤维是如何随着时间的推移而保持的，我们正在探索弹性假黄瘤的病理机制，这是一种遗传性疾病，其特征是进行性弹性纤维断裂和钙化。

DESCRIPTION (provided by applicant): 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.