ELASTIN GENE MUTATIONS IN SKIN AND VASCULAR DISEASES

本提案的总体目标是了解弹性蛋白基因突变在两种弹性组织遗传性疾病，即瓣上主动脉瓣狭窄（SVAS）和常染色体显性皮肤松弛症（ADCL）的发病和病理生物学中的作用。弹性蛋白是弹性纤维中的主要蛋白质，负责包括皮肤和血管在内的所有弹性组织的反冲特性。在过去的几年里，包括我们在内的几位研究人员已经证明，弹性蛋白基因的突变是导致两种表型不同的遗传性疾病的原因。SVAS是一种常染色体显性血管疾病，主要表现为动脉壁狭窄，无明显的肺或皮肤表型。相反，ADCL主要是一种皮肤疾病，其特征是皮肤无弹性，伴有少量血管疾病。这两种疾病最近都被证明是由弹性蛋白基因突变引起的。虽然目前尚不清楚该基因的突变如何导致两种不同的疾病，但从提案中提出的初步结果来看，似乎弹性蛋白基因突变的性质将决定血管或皮肤表型。我们在本提案中概述的四个具体目标旨在阐明弹性蛋白基因突变类型与这些突变对组织形态发生、弹性蛋白纤维组装和弹性蛋白组织功能的影响之间的详细关系。弹性蛋白基因表达的变化是许多常见的弹性组织疾病的一个特征，从主动脉瘤到瘢痕疙瘩，我们期望从我们提出的SVAS和ADCL的工作中获得新的见解，对更好地理解这些更常见的结缔组织疾病的发病机制产生重大影响。

The overall goal of this proposal is to understand the role of mutations in the elastin gene in the pathogenetics and pathobiology of two heritable diseases of elastic tissue, supravalcualar aortic stenosis (SVAS) and autosomal dominant cutis laxa (ADCL). Elastin is the major protein in elastic fibers and responsible for the recoil properties of all elastic tissues, including skin and blood vessels. Over the last few years, several investigators, including ourselves, have demonstrated that mutations in the elastin gene are responsible for two phenotypically distinct heritable disorders. SVAS is an autosomal dominant vascular disease characterized principally by arterial wall stenosis, with no obvious pulmonary or dermal phenotype. In contrast, ADCL is primarily a skin disorder characterized by inelastic skin with minimal vascular disease. Both disease have been shown recently to be due to mutations in the elastin gene. While it is not clear how mutations in the gene will result in two separate diseases, from preliminary results presented in the proposal, it seems that the nature of the mutations in the elastin gene will determine either a vascular or a dermal phenotype. The four specific aims that we have outlined in this proposal are intended to elucidate the detailed relationship between the type of mutations in the elastin gene and the influence of these mutations on both tissues morphogenesis, and elastin fiber assembly and elastin tissue function. Changes in elastin gene expression are a characteristic feature of many common elastic tissue disorders ranging from aortic aneurysms to keloids and we expect new insights from our proposed work on SVAS and ADCL to have a significant effect on a better understanding of the pathogenesis of these more common connective tissue disorders.