| Budget Amount *help |
¥12,800,000 (Direct Cost: ¥12,800,000)
Fiscal Year 2002: ¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 2001: ¥4,000,000 (Direct Cost: ¥4,000,000)
Fiscal Year 2000: ¥5,600,000 (Direct Cost: ¥5,600,000)
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| Research Abstract |
Clinical gene therapy was required more fundamental and clinical evidences for safety since 3-lymopoproliferative disease had been reported in A. Fischer's gene therapy protocol for X-SCID patients. More than 200 patients with chronic granulomatous disease (CGD) were first analyzed and a genetic mechanisms of IFN-gamma responsibility was analyzed in the patients with the splice mutation of gp91-phox deficiency (Blood 98 : 436-441, 2001).
In our 3-year's project, collaborating with Dr. Sugimoto, we constructed a bicistronic retrovirus vector, Ha-MDR-IRES-gp91, for the co-expression of MDR1 and gp91, a gene responsible for X-linked chronic granulomatous disease (X-CGD). Epstein-Barr virus-transformed B cells from X-CGD patients and human CD34-positive cells from an X-CGD patient transduced with Ha-MDR-IRES-gp91 co-expressed P-glycoprotein and gp91, and acquired superoxide-generating activity. Mice transplanted with Ha-MDR-IRES-gp91-transduced bone marrow cells showed co-expression of P-gl
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ycoprotein and gp91 in peripheral blood mononuclear cells. After repeatedly administration of paclitaxel, the ratio of P-glycoprotein- and gp91-positive cells were maintained for over 1 year. These results suggest that co-expression of a human multidrug resistance gene (MDR1) with a therapeutic gene affords selectable growth advantage to genetically modified cells (J Gene Med vol. 4, 2003).
In a collaboration with Dr. Sumimoto, we clarified the fourth cytosolic factor p40 (phox) participates in activation of the phagocyte oxidase by regulating membrane recruitment of p67 (phox) and p47 (phox) via the PB1-PC interaction with p67 (phox). (EMBO J 2002 Dec 2 ; 21(23) : 6312-20). In addition, we cloned human cDNAs for novel proteins homologous to p47phox and p67phox, designated p41nox and p51nox, respectively. Based on the combination studies, we found that the novel homologues p41nox and p51nox likely function together or in combination with a classical one, thereby activating the two Nox family oxidases (J Biol Chem 2003 in press). Less
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