ELASTIC FIBER DEFECTS IN PSEUDOXANTHOMA ELASTICUM

这项建议的目的是了解弹性纤维缺陷在皮肤、血管和眼组织的遗传性疾病中的生物学和病理基础，弹性假黄瘤(PXE)。PXE是一种遗传性疾病，其特征是异常弹性纤维在几个弹性组织中聚集，特别是皮肤、动脉和视网膜的弹性Bruchs膜。这些组织中钙化弹性纤维的异常沉积是PXE临床症状发展的原因，这些症状包括弹力性皮肤损害、伴有部分视力丧失的视网膜出血和血管缺陷，如胃肠道出血和心肌梗死。PXE的遗传方式复杂，常染色体显性遗传和隐性遗传均有报道。在过去的几年里，几个研究小组试图确定导致PXE的基因突变(S)，但直到最近两年，包括我们自己在内的三个不同的实验室才在16号染色体短臂上定位了一个导致PXE的主要基因座。我们现在成功地确定了820kb的16p13.1处包含6个候选基因的区域，其中至少一个包含导致PXE的突变。利用这一新信息，我们希望在一组PXE患者中识别PXE基因，即该基因的突变，并确定PXE基因产物的可能功能。这些目标侧重于阐明PXE的生物学，并利用这些信息更好地了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，如皮肤、动脉瘤、动脉粥样硬化和老年性黄斑变性等许多营养不良性钙化疾病。

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.