ELASTIC FIBER DEFECTS IN PSEUDOXANTHOMA ELASTICUM

本建议的目的是了解皮肤，血管和眼部组织，弹性假黄瘤（PXE）的遗传性疾病的弹性纤维缺陷的生物学和发病机制的基础。PXE是一种遗传性疾病，其特征在于异常弹性纤维在几种弹性组织中的积累，特别是皮肤、动脉和视网膜的弹性布鲁赫膜。 钙化弹性纤维在这些组织中的异常沉积导致了PXE的临床症状特征的发展，这些症状包括无弹性皮肤病变、视网膜出血伴部分视力丧失和血管缺陷如胃肠道出血和心肌梗死。 PXE的遗传模式是复杂的，常染色体显性和隐性形式的疾病已被报道。 在过去的几年里，几组研究人员试图确定导致PXE的基因突变，但只是在过去的两年里，包括我们自己的实验室在内的三个独立的实验室才在16号染色体的短臂上找到了这种疾病的主要基因座。我们现在已经成功地确定了在16p13.1的820kb的区域，包含6个候选基因，其中至少一个将包含负责PXE的突变。 有了这些新的信息，我们希望能够确定“PXE基因”，在一组PXE患者中该基因的突变，并确定PXE基因产物的可能功能。这些目标集中于阐明PXE的生物学，并使用这些信息来更好地理解弹性纤维在更常见的弹性组织疾病中的作用，特别是那些以组织钙化为特征的皮肤、血管和眼部疾病，例如皮肤的许多营养不良性钙化疾病、动脉瘤、动脉粥样硬化和年龄相关性黄斑变性。

The aim of this proposal is to understand the biological and pathogenetic basis of elastic fiber defects in a heritable disorder of cutaneous, vascular and ocular tissue, pseudoxanthoma elasticum (PXE). PXE is a heritable disease characterized by the accumulation of abnormal elastic fibers in several elastic tissues, particularly the skin, arteries and the elastic Bruch's membrane of the retina. The aberrant deposition of calcified elastic fibers in these tissues is responsible for the development of the clinical symptoms characteristic of PXE and these include inelastic skin lesions, retinal hemorrhage with partial loss of vision and vascular defects such as gastrointestinal bleeding and myocardial infarction. The pattern of inheritance of PXE is complex and both autosomal dominant and recessive forms of the disease have been reported. Over the last few years, several groups of investigators have attempted to identify the gene mutation(s) responsible for PXE but it has only been in the last two years that three separate laboratories, including our own, have located a major locus for this disease on the short arm of chromosome 16. We have now successfully identified a region at 16p13.1 of 820kb that contains 6 candidate genes, at least one of which will contain the mutations responsible for PXE. With this new information, we hope to identify the 'PXE gene', the mutations in this gene in a cohort of PXE patients and determine a possible function for the product of the PXE gene. These goals are focused on elucidating the biology of PXE and using this information to provide a better understanding of the role of elastic fibers in more common elastic tissue diseases, particularly those skin, vascular and eye disorders characterized by tissue calcification such as the many dystrophic calcification disorders of skin, aneurysms, atherosclerosis and age-related macular degeneration.