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识别和表征导致弹性假黄瘤（PXE）弹性纤维改变和钙化的分子事件，作为相关的疾病模型，以更好地理解控制弹性纤维超组装和动态平衡的动力学。这些大而复杂的分子为弹性组织提供机械特性，并在许多发育中的组织中调节细胞命运。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。弹性假黄瘤（PXE）是一种以弹性纤维断裂和钙化为特征的遗传性疾病。长期以来，PXE被认为是一种典型的结缔组织疾病，但PXE的表型出人意料地与一个显然与弹性纤维无关的基因（ABCC6）有关。我们已经获得了初步的结果，表明PXE患者血清中的循环因子改变了体外弹性纤维的形成。这些数据表明PXE是一种继发性细胞外基质重塑的代谢性疾病，循环因子可能参与或加剧该疾病表型的发展。因此，我们假设血液中出现的异常循环因子是ABCC6无法输出其底物的次要后果；这些PXE因子随后从循环中渗透到结缔组织中，阻止弹性纤维的初始沉积或促进结构改变，最终导致其钙化。为了验证这一假设，我们提出了两个具体的目标，分别是：(1)在真皮成纤维细胞培养中，PXE患者血清诱导的弹性纤维缺陷的分子特征；(2)鉴定导致这些缺陷的血清因子。我们期望我们提出的实验将导致识别干扰弹性纤维的因素，并可能开发缓解PXE症状的治疗措施。我们也期望从我们的研究中对维管组织中弹性纤维的形成和老化有一个新的认识。公共卫生相关性：弹性纤维是大而复杂的分子，通过为弹性组织提供特定的机械性能而对生命至关重要。为了了解弹性纤维是如何随着时间的推移而维持的，我们正在探索弹性假黄瘤的病理机制。弹性假黄瘤是一种遗传性疾病，其特征是弹性纤维逐渐断裂和钙化。

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.