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Basic Studies on Gene Therapy for Glomerulonephritis

肾小球肾炎基因治疗基础研究

基本信息

批准号：
07671245
负责人：
NAKAGAWA Yoichi
金额：
$ 1.02万
依托单位：
Department of Medicine, Niigata University School of medicene
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1996
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07671245/
关键词：
Alport syndrome benign familial hemeturia thin basement membrane disease type IV collagen protooncogene transcriptional factors Thy-1,1 nephrits all-trans retinoic acid 非薄基底膜病病原遺伝子 Thy-1腎炎 5 6腎摘 c-myc NF-kB AP-1

项目摘要

1) Genetic analysis of hereditary renal diseasesWe have analyzed the genomic DNA from Alport syndrome patients, which is characterized by specific morphological changes of glomerular basement membrane such as basket weave appearance. We have identified the deletion of type IV collagen alpha 5 chain from 3 patients. Two cases had partial deletion and another was supposed to have complete deletion of the alpha 5 and alpha 6 chains.Benign familial hematuria is also known as thin basement membrane disease (TBMD) and characterized by diffuse thinning of lamina densa of the glomerular basement membrane. We have performed the genetic linkage analysis between type IV collagen alpha 3 or alpha 4 chain and TBMD.But there was no linkage, suggesting the genes responsible for TBMD were other than these basement membrane collagens.2) Transcriptional factors in rat experimental glomerulonephritisWe have focused on protooncogenes such as c-fos, c-jun and c-myc, and AP-1 which is heterodimer complex of … More c-Fos and c-Jun, in rat anti Thy 1,1 nephritis and streptozotocin diabetic rats.mRNA expression for c-myc was maximal at 4 or 5 days after the induction anti Thy 1,1 nephritis, which phase is cosistent with mesangial cell proliferation. AP-1 complex expressed srtrongly in the chronic, glomeruloscrelotic phase of STZ diabetic rats rather than just after the induction of the diabetes. These results reveald that these transcriptional factors play an important roles in mesangial proliferative glomerulonephritis, especially in the progressive and chronic phase of the disease.3) Effects of all trans retinoic acid (ATRA) on mesangial cellsATRA is known as an inducer of cell differentiation. This may suggests that ATRA induces growth suppression of mesangial cells via the induction of phenotypic change of the cells.We have analyzed the effects of ATRA on cultured mesangial cells. ATRA suppressed the mesangial cell growth and mRNA expressions for c-fos, c-jun and c-myc. Then we administerd ATRA torats of anti Thy 1,1 nephritis. Mesangial cell number and matix score were significantly suppressed in ATRA treated rats. These results strongly suggested that the down regulation of these transcriptional factors could be a possible candidate for the treatment of mesangial proliferative glomerulonephritis. Less

1)遗传性肾脏疾病的遗传学分析我们对Alport综合征患者的基因组DNA进行了分析，其特征是肾小球基底膜的特殊形态学改变，如篮子编织外观。我们已经确定了3例患者IV型胶原α 5链缺失。良性家族性血尿又称薄基底膜病（thin basement membrane disease，TBMD），以肾小球基底膜致密层弥漫性变薄为特征。我们对Ⅳ型胶原α 3或α 4链与TBMD进行了遗传连锁分析，但未发现连锁，提示TBMD的致病基因并非这些基底膜胶原。2）大鼠实验性肾小球肾炎的转录因子我们重点研究了原癌基因c-fos、c-jun和c-myc以及AP-1，AP-1是一种转录因子的异源二聚体复合物。 ...更多信息 c-Fos和c-Jun在抗Thy 1，1肾炎和链脲佐菌素糖尿病大鼠中的表达，c-myc mRNA表达在抗Thy 1，1肾炎后4或5天达高峰，与系膜细胞增殖相一致。AP-1复合物在STZ糖尿病大鼠慢性肾小球硬化期表达较强，而不是在糖尿病诱导后才表达。这些结果提示这些转录因子在系膜增生性肾小球肾炎中起重要作用，尤其是在疾病的进展期和慢性期。3）全反式维甲酸（ATRA）对系膜细胞的作用ATRA是一种细胞分化诱导剂。这可能提示全反式维甲酸通过诱导系膜细胞表型改变而抑制系膜细胞的生长。ATRA抑制系膜细胞生长及c-fos、c-jun、c-myc mRNA表达。抗Thy 1，1肾炎用ATRA治疗。ATRA组大鼠肾小球系膜细胞数和基质评分明显降低。这些结果有力地表明，这些转录因子的下调可能是一个可能的候选治疗系膜增生性肾小球肾炎。少