ADPKD Connective Tissue Disorder Link

ADPKD 结缔组织疾病链接

• 批准号: 7230235
• 负责人: ROBERT L BACALLAO
• 金额: $ 14.71万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7230235
• 关键词: Accounting; Address; Affect; Affinity; Anabolism; Antibodies; Architecture; Autosomal Dominant Polycystic Kidney; Autosomal Recessive Polycystic Kidney; Binding; Biogenesis; Blood Vessels; Buffers; Cardiovascular Abnormalities; Cell Proliferation; Cells; Chromosomes, Human, Pair 15; Chromosomes, Human, Pair 16; Coculture Techniques; Code; Condition; Congenital Heart Defects; Connective Tissue Diseases; Cyst; Cystic kidney; Data; Dialysis procedure; Disease; Ectopic Expression; Elastin; Electron Microscopy; Employee Strikes; Epithelial; Epithelial Cell Proliferation; Epithelial Cells; Extracellular Matrix; Extracellular Matrix Proteins; FBN1; Family; Fibroblasts; Genes; Genetic; Genomics; Goals; Growth; Guanidinium Chloride; Higher Order Chromatin Structure; Human; Immunoblotting; Immunofluorescence Immunologic; Immunohistochemistry; Inherited; Investigation; Kidney; Kidney Failure; Kidney Glomerulus; Knockout Mice; Label; Laboratories; Lead; Lens dislocation; Link; Localized; Maintenance; Marfan Syndrome; Microfibrils; Modeling; Molecular; Morphogenesis; Mutation; Myopia; Names; Normal tissue morphology; Numbers; Pathogenesis; Patients; Pattern; Peptide antibodies; Phenotype; Physical Dialysis; Polycystic Kidney Diseases; Polymerase Chain Reaction; Process; Protein Biosynthesis; Proteins; Public Health; Rattus; Recombinants; Role; Source; Staging; Structure; System; Testing; Tissues; Transcript; Triton X100; Tubular formation; Tunica Media; United States; Ursidae Family; Vascular Permeabilities; cell growth; cell type; extracellular; fetal; fibrillin-2; gene cloning; human microfibrillar-associated protein 2; interest; interstitial; member; microfibrillar protein; nephrogenesis; novel; protein expression; scoliosis; size; subcutaneous

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.

描述（申请人提供）：我们发现了一种新型微原纤维蛋白，称为血管基质蛋白（VMP），它广泛表达于大到中型血管的中膜中。我们的证据表明，这种蛋白质是由 PKD1 基因座（编码基因）产生的替代转录物。多项证据支持 VMP 是基质微原纤维的组成部分这一结论。从组织中提取 VMP 所需的条件与其他微原纤维成分（如原纤维蛋白 1、2、微原纤维相关糖蛋白和弹性蛋白）所描述的条件类似。通过免疫组织化学和电子显微镜测定，VMP 与原纤维蛋白-1、原纤维蛋白-2、弹性蛋白和微原纤维相关糖蛋白 (MAGP-1) 共定位。使用 6 M 氯化胍进行组织蚀刻可优化抗 VMP 组织的免疫荧光标记。 VMP 的发现可能解释了 ADPKD 的肾外表现，其与结缔组织疾病有相似之处。 VMP 突变也可能解释了 2 个患有 ADPKD 和结缔组织疾病的家族。引人注目的是，这些家族在表型上类似于马凡表型，但它们的重叠结缔组织疾病与 16 号染色体上的 PKD1 基因座相关（Somlo 等人，JASN，第 4 卷，1371-8，1993）。编码细胞外基质微纤维的另一种转录物的鉴定也可以解释这样的发现：通过删除 PKD1 3' 端而产生的 PKD1 敲除小鼠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 等人，PNAS，第 97 卷，1731-35， 2000）。 VMP仅在肾囊肿形成的情况下在肾间质中异位表达。这表明 VMP 表达与导致囊肿形成的上皮生长异常有关。该提案的目标是明确鉴定编码 VMP 的基因，确定 VMP 的生物发生并检查其在囊肿发生或肾发生中的潜在作用。与公众健康的相关性——多囊肾病是美国肾衰竭最常见的遗传原因。更好地了解疾病过程将有助于找到阻止肾衰竭进展的治疗方法，从而减少透析患者的数量。

项目成果

Characterization of the renal cyst fluid proteome in autosomal dominant polycystic kidney disease (ADPKD) patients.

• DOI: 10.1002/prca.200780140
• 发表时间: 2008-07-01
• 期刊: PROTEOMICS CLINICAL APPLICATIONS
• 影响因子: 2
• 作者: Lai, Xianyin;Bacalla, Robert L.;Blazer-Yost, Bonnie L.;Hong, David;Mason, Stephen B.;Witzmann, Frank A.
• 通讯作者: Witzmann, Frank A.