1996 Fiscal Year Final Research Report Summary
in vivo transfection into the kidney and application of gene therapy
| Project/Area Number |
07457241
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Kidney internal medicine
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| Research Institution | NARA Institute of Science and Technology |
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Principal Investigator |
UEDA Naohiko NARA Institute of Science and Technology Professor, 保健管理センター, 教授 (70115997)
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| Co-Investigator(Kenkyū-buntansha) |
IMAI Enyu Osaka Univ.Sch.Med.Assistant professor, 医学部, 助手 (00223305)
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| Project Period (FY) |
1995 – 1996
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| Keywords | glomerulonephritis / TGF-beta / antisense oligonucleotide / HVJ-liposome / decorin / gene therapy |
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| Research Abstract |
Transforming growth factor-beta (TGF-beta) has been implicated in the pathogenesis of fibrotic diseases. TGF-beta was shown to play a crucial role in the accumulation of extracellular matrix in a rat model of acute mesangial proliferative glomerulo-nephritis induced by injection of anti-thymocyte serum (ATS). And sustained expression of TGF-beta was suggested to contribute to the development of kidney fibrosis. Here we report two therapeutic strategies to manipulate the action of TGF-beta1 in the nephritic glomeruli. First, in order to inhibit the overproduction of TGF-b1 in the nephritic glomeruli, we intoduced antisense oligodeoxynucleotides (ODNs) for TGF-b1 into the nephritic kidney by HVJ-liposome mediated gene transfer method. This fusogenic liposome can directly introduce the materials encapsulated inside into cytoplasm through membrane fusion. Thus, transfected ODNs rapidly accumulated in the nuclei of mesangial cells in the glomeruli, where TGF-beta is highly expressed in a autocrine fashion. Second, we examined to introduce decorin, a small proteoglycan, gene into the muscle of the nephritic rats in order to block the TGF-beta activity by competeing with the receptors for the binding of active TGF-beta in the glomeruli. We hypothesized that transfecting the decorin gene into skeletal muscle would increase the muscle's production and secretion of decorin protein into the blood where it would be delivered to the kidney. We observed that transfection of decorin cDNA into the skeletal muscle of normal or glomerulonephritic rats increases the amount of immunoreactive decorin present in the kidney and other organs, confirming our hypothesis. Transfected glomerulonephritic rats showed a significant inhibition of glomerular TGF-beta activity, with a comparable effect in the reduction of extracellular matrix accumulation and proteinuria. These results suggest that gene therapy might be clinically useful for glomerulosclerosis with TGF-beta overproduction.
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Research Products
(12 results)
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[Publications] Akagi Y,Isaka Y,Arai M,Kaneko T,Takenaka T,Moriyama T,Kaneda Y.Ando, Orita Y,Kamada T,Ueda N,Imai E.: "Inhibition of transforming growth factor-beta1 expression by antisense oligonucleotides suppressesd extracellular matrix accumulation in experimental glomerulonephritis." Kidney Int. 50. 148-155 (1996)
Description
「研究成果報告書概要(欧文)」より
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[Publications] Imai E,Isaka Y,Akagi Y,Arai M,Moriyama T,Takenaka M,Kaneko T,Horio M,Nado A,Orita Y,Kaneda Y,Ueda N,Kamada T.: "Application of antisense oligonucleotides (ODNs) for the intervention of kidney disease." Contribution to Nephrology. 118. 86-93 (1996)
Description
「研究成果報告書概要(欧文)」より
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[Publications] Akagi Y,Isaka Y,Akagi A,Ikawa M,Takenaka M,Moriyama T,Yamauchi A,Horio M,Ueda N,Okabe M,and Imai E.D: "Transcriptional activation of a hybrid promoter composed of cytomehalovirus enhancer and b-actin/b-globin gene in glomerular epithelial cells in vivo" Kidney Int.(in press).
Description
「研究成果報告書概要(欧文)」より
