ADPKD Connective Tissue Disorder Link

ADPKD 结缔组织疾病链接

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：我们发现了一种新型的微纤维蛋白，称为血管基质蛋白（VMP），该蛋白在大到中型血管的介质中广泛表达。我们的证据表明，该蛋白是由PKD1基因座（代码的基因）引起的替代转录本。几条证据支持VMP是基质微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（例如纤维蛋白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子显微镜确定的VMP与原纤维素-1，Fibrillin-1，Fibrillin-2，弹性蛋白和与微纤维相关的糖蛋白（MAGP-1）共定位。用氯化物6 M蚀刻的组织蚀刻可优化用抗VMP组织的免疫荧光标记。 VMP的发现可能解释了与结缔组织疾病具有相似之处的ADPKD的肾外表现。 VMP中的突变还可以解释2个患有ADPKD和结缔组织障碍的家庭的描述。令人惊讶的是，这些家族在表型上类似于Marfan表型，但它们与16号染色体上的PKD1基因座相关的重叠结缔组织障碍（Somlo等，Jasn，Jasn，第4卷，1371-8，1993）。识别另一个编码的转录本，该转录物编码为细胞外基质微纤维编码，也可能解释了以下发现：PKD1敲除小鼠由PKD1的3'末端的缺失产生的PKD1敲除小鼠具有胎儿致死表型，这是由于血管渗透性增加而导致的胎儿致死性表型，心脏缺陷，心脏缺陷，心脏缺陷和皮下注射下39.kim1-kim 397（Kim 3）（Kim 397），pn ass anas et al.pn。 2000）。 VMP仅在肾脏囊肿形成的环境中在肾脏间质中被异位表达。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识别编码VMP的基因，确定VMP的生物发生，并检查其在囊肿发生或肾脏形成中的潜在作用。与公共卫生型肾脏疾病相关的是美国肾衰竭最常见的遗传原因。更好地了解疾病过程将导致疗法停止肾衰竭的进展，从而减少透析患者的数量。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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.