| Budget Amount *help |
¥38,200,000 (Direct Cost: ¥38,200,000)
Fiscal Year 2000: ¥17,500,000 (Direct Cost: ¥17,500,000)
Fiscal Year 1999: ¥20,700,000 (Direct Cost: ¥20,700,000)
|
|---|
| Research Abstract |
Hemodialysis due to end-stage renal diseases is a major social and economic problem in Japan because about 170,000 patients are treated at present, and the number has been increasing by about 13,000 every year. and because the medical expenses for the treatment of dialysis patients has risen up to more than a trillion U.S.dollars per year which takes up approximately four percent of total medical expenses in Japan. Chronic glomerulonephritis and diabetic nephropathy are two major underlying diseases which account for about 80% of the total number of patients with renal insufficiency. However, their exact mechanisms are still unknown at the molecular levels and therefore there is no effective therapy. The purposes of the projects in progress in our laboratory is 1) to elucidate the molecular pathogenesis of renal diseases, such as chronic glomerulonephritis and diabetic nephropathy, and 2) to develop novel therapeutic approaches to prevent or retard the progression of renal diseases.
Mes
… More
angial cells play an important role in maintaining a structure and function of the glomerulus and in the pathogenesis of glomerular diseases. The proliferation of mesangial cells and the accumulation of extracellular mesangial matrix are primary events leading to the progression to glomerulosclerosis in patients with a variety of glomerular disorders such as chronic glomerulonephritis and diabetic nephropathy, two major causes of end-stage renal failure. The purposes of the present study were 1) to perform a molecular biological quantification of genes expressed in cultured human mesangial cells and 2) to identify specific genes expressed in mesangial cells. To obtain quantitative information of expressed genes in mesangial cells, we employed a 3'-directed regional cDNA library from human mesangial cells. With this approach, we can avoid variable cloning efficiencies reflecting the size of cDNA.we randomly chose almost 2000 transformant colonies, amplified their cDNA moieties by PCR and determined their cDNA sequences. Since the sequences at the 3'-region are unique, sequencing data from about 150-300 nucleotides were sufficient to characterize the gene. Redundancy of the same sequence represents the abundance of corresponding transcript in cells. The "expression profiles" in mesangial cells were apparently different from those obtained from other libraries, which confirmed specificity of "expression profiles" in different cells and organs. And, we identified 5 unknown genes, termed megsin, meg-1, -2, -3, and -4, specifically expressed in mesangial cells.
Megsin is a new member of the serine protease inhibitor (serpin) superfamily. Our previous studies strongly suggest the role of megsin in the pathogenesis of human glomerular diseases, but its exact biological significance has not been clear. We produce human megsin transgenic mice. Overexpression of megsin leads to progressive mesangial matrix expansion and to an increase in the number of mesangial cells. Megsin has thus a biologically relevant influence on mesangial function. Less
|
