ADPKD Connective Tissue Disorder Link

描述（由申请人提供）：我们发现了一种新的微纤维蛋白，称为血管基质蛋白（VMP），广泛表达于大中型血管介质中。我们的证据表明，该蛋白是由PKD1位点产生的另一种转录物，该基因编码。有几条证据支持VMP是基质微原纤维的组成部分的结论。从组织中提取VMP需要类似于其他微纤维成分（如原纤维蛋白1、2、微纤维相关糖蛋白和弹性蛋白）的条件。通过免疫组织化学和电镜检测，VMP与纤维蛋白-1、纤维蛋白-2、弹性蛋白和微纤维相关糖蛋白（MAGP-1）共定位。组织蚀刻与6 M氯化胍优化免疫荧光标记组织与抗vmp。VMP的发现可能解释了ADPKD与结缔组织疾病相似的肾外表现。VMP突变也可能解释了2个ADPKD和结缔组织疾病家族的描述。引人注目的是，这些家族在表型上与马凡表型相似，但它们的重叠结缔组织疾病与16号染色体上的PKD1位点相关（Somlo等人，JASN, vol 4, 1371- 8,1993）。鉴定另一种编码细胞外基质微纤维的转录本也可以解释PKD1基因敲除小鼠（由PKD1 3'端缺失产生）由于血管通透性增加、心脏缺陷和皮下出血而具有胎儿致死表型（Kim etal .， PNAS, vol 97, 1731- 35,2000）。VMP仅在肾囊肿形成时异位表达于肾间质。这表明VMP表达与导致囊肿形成的上皮生长异常有关。本提案的目标是明确识别编码VMP的基因，确定VMP的生物发生，并检查其在膀胱发生或肾脏发生中的潜在作用。在美国，多囊肾病是肾衰竭最常见的遗传原因。对疾病过程的更好理解将导致阻止肾衰竭进展的治疗，从而减少透析患者的数量。

DESCRIPTION (provided by applicant): We have discovered a novel microfibril protein, named vascular matrix protein (VMP) which is extensively expressed in the media of large to medium sized blood vessels. Our evidence indicates that this protein is an alternative transcript arising from the PKD1 locus, the gene that codes for. Several lines of evidence support the conclusion that VMP is a component of matrix microfibrils. Extraction of VMP from tissue requires conditions similar to that described for other microfibril components such as fibrillin 1, 2, microfibril associated glycoprotein and elastin. VMP co-localized with fibrillin-1, fibrillin-2, elastin and microfibril associated glycoprotein (MAGP-1) as determined by immunohistochemistry and electron microscopy. Tissue etching with 6 M guanidinium chloride optimizes immunofluorescence labeling of tissue with anti-VMP. Discovery of VMP may account for the extra-renal manifestations of ADPKD which bears similarities to connective tissue disorders. Mutations in VMP may also account for the description of 2 families with ADPKD and connective tissue disorders. Strikingly these families phenotypically resemble a Marfan phenotype, yet their overlap connective tissue disorder linked to the PKD1 locus on chromosome 16 (Somlo et al., JASN, vol 4, 1371-8, 1993). Identification of another transcript encoded which codes for an extracellular matrix microfibril may also explain the finding that PKD1 knockout mice, generated by deletions from the 3' end of PKD1, have a fetal lethal phenotype due to increased vascular permeability, cardiac defects and subcutaneous hemorhages (Kim et al., PNAS, vol 97, 1731-35, 2000). VMP is ectopically expressed in the renal interstitium only in the setting of kidney cyst formation. This suggests that VMP expression is linked to epithelial growth abnormalities that lead to cyst formation. The goals of this proposal are to unambiguously identify the gene that codes for VMP, determine the biogenesis of VMP and examine its potential role in cystogenesis or nephrogenesis. RELEVANCE TO PUBLIC HEALTH-Polycystic kidney disease is the most common genetic cause of renal failure in the United States. Better understanding of the disease process will lead to therapies that halt progression of renal failure thereby decreasing the number of patients on dialysis.