Pseudoxanthoma elasticum: Elastic fibers alterations and characterization of seru

弹性假黄瘤：弹性纤维改变和血清特征

• 批准号: 7740288
• 负责人: OLIVIER LE SAUX
• 金额: $ 18.75万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7740288
• 关键词: ATP-Binding Cassette Transporters; Adult; Affect; Age; Aging; Animal Model; Aorta; Atherosclerosis; Biological Assay; Biology; Blood; Blood Circulation; Blood Vessels; Cell Line; Cells; Characteristics; Chronic Kidney Failure; Complex; Connective Tissue; Connective Tissue Diseases; Culture Media; Data; Defect; Deposition; Dermal; Development; Disease; Disease model; Elastic Fiber; Elastic Tissue; Elastin; Electron Microscopy; Etiology; Event; Extracellular Matrix; FBN1; Failure; Fiber; Fibroblasts; Fractionation; Genes; Goals; Homeostasis; Human; In Vitro; Individual; Injury; Kidney; LOX gene; Lead; Life; Light; Link; Liver; Maintenance; Mass Spectrum Analysis; Measures; Mechanics; Metabolic Diseases; Microfibrils; Molecular; Mutation; Natural regeneration; Nature; Pathologic; Pathology; Patients; Peptide Hydrolases; Phenotype; Process; Production; Property; Proteins; Protocols documentation; Pseudoxanthoma Elasticum; Serum; Skin; Smooth Muscle Myocytes; Staging; Symptoms; Testing; Time; Tissues; base; calcification; disease phenotype; fibulin-4; in vivo; public health relevance; repaired; research study; structural biology; therapeutic development

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.

描述（由申请人提供）：本申请的具体目标是识别和表征分子事件，导致弹性纤维改变和假性氧化瘤弹性瘤（PXE）作为相关疾病模型，以更好地了解弹性纤维弹性纤维的超级组装和稳态的动态。这些是大型复杂的分子，可为弹性组织提供机械性能，并调节许多发育中的组织中的细胞命运。这些纤维对于生命的发展至关重要，但是尚未完全理解它们的组装和维护方式。假阳性瘤（PXE）是一种可遗传的疾病，其特征是弹性纤维破碎和钙化。长期以来，人们认为PXE是一种原型结缔组织疾病，但PXE表型意外地与显然与弹性纤维无关的基因（ABCC6）相关。我们获得了初步结果，表明PXE患者血清的循环因子在体外改变了弹性纤维的形成。该数据表明，PXE是一种具有继发细胞外基质重塑的代谢疾病，循环因子可能会参与或加剧疾病表型的发展。因此，我们假设血液中异常的循环因子是由于ABCC6未能导出其底物的第二结果。然后，这些PXE因子（S）从循环中渗透到结缔组织中，并排除弹性纤维的初始沉积或促进结构改变，最终导致其钙化。为了检验这一假设，我们建议实现与（i）相对应的两个具体目的，该目标与（i）由PXE患者存在于皮肤成纤维细胞培养的PXE患者中诱导的弹性纤维缺陷（II）鉴定有关这些缺陷的血清因子的识别。我们预计我们提出的实验将导致识别因素干扰弹性纤维的因素，并可能开发出减轻PXE症状的治疗措施。我们还可以从研究中预期对血管组织中弹性纤维形成和衰老的新水平。公共卫生相关性：弹性纤维是大型复杂的分子，通过为弹性组织提供特定的机械性能，对生命很重要。为了了解弹性纤维如何随着时间的流逝而保持，我们正在探索假氧化瘤弹性的病理机制，一种可遗传的疾病，其特征是进行性弹性纤维碎片和钙化。