| Project/Area Number |
14207031
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (A)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Neurology
|
|---|
| Research Institution | Kagoshima University |
|---|
Principal Investigator |
OSAME Mitsuhiro Kagoshima University, Graduate School of Medical and Dental Sciences, Professor, 大学院・医歯学総合研究科, 教授 (10041435)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
ARIMURA Kimiyoshi Kagoshima University, Graduate School of Medical and Dental Sciences, Associate Professor, 大学院・医歯学総合研究科, 助教授 (20159510)
UMEHARA Fujio Kagoshima University, Graduate School of Medical and Dental Sciences, Assistant Professor, 大学院・医歯学総合研究科, 講師 (20271140)
KUBOTA Ryuji Kagoshima University, Graduate School of Medical and Dental Sciences, Associate Professor, 大学院・医歯学総合研究科, 助教授 (70336337)
IZUMO Shuji Kagoshima University, Graduate School of Medical and Dental Sciences, Professor, 大学院・医歯学総合研究科, 教授 (30143811)
USUKU Koichiro Kagoshima University, Graduate School of Medical and Dental Sciences, Associate Professor, 大学院・医歯学総合研究科, 助教授 (30281223)
|
|---|
| Project Period (FY) |
2002 – 2004
|
| Project Status |
Completed (Fiscal Year 2004)
|
| Budget Amount *help |
¥37,050,000 (Direct Cost: ¥28,500,000、Indirect Cost: ¥8,550,000)
Fiscal Year 2004: ¥9,360,000 (Direct Cost: ¥7,200,000、Indirect Cost: ¥2,160,000)
Fiscal Year 2003: ¥12,480,000 (Direct Cost: ¥9,600,000、Indirect Cost: ¥2,880,000)
Fiscal Year 2002: ¥15,210,000 (Direct Cost: ¥11,700,000、Indirect Cost: ¥3,510,000)
|
|---|
| Keywords | HTLV-I-associated myelopathy / HTLV-I proviral load / Therapy / Prognosis / metalloproteinase inhibitor / susceptible genes / cytotoxic T lymphocytes / 予後判定 / dN / dS比 / 治療薬開発 / 高齢発症 / MMP / MMP阻害剤 / HTLM-Iプロウイルス量 |
|---|
| Research Abstract |
In this research project, we have deeply improved our understanding for the pathogenesis of HTLV-I-associated myelopathy(HAM) and developed a hopeful therapy for the disease. It is an initial event that HTLV-I-infected cells infiltrate into the central nervous system for the development of HAM, where matrix metalloproteinase(MMP)-2 and -9 play an important role. We found that a selective MMP inhibitor specific for MMP-2 and -9, N-Biphenyl sulfonyl-phenylalanine hydroxamic acid(BPHA), significantly inhibited migration activity of CD4+ T lymphocytes (which are a main reservoir of HTLV-I) from HAM patients. This suggests that the compound is a candidate for a new therapy for HAM patients. We had identified many genetic factors which increase susceptibility for the disease, and we newly identified two genetic factors, polymorphism of interleukin-10 promoter, and the length of tandem repeat in MMP-9 promoter. Using these host genetic factors, we made a formula to predict the risk of the development of HAM. When we utilized it for HTLV-I asymptomatic carriers, the carriers with high risk values showed faint abnormalities on the neurological examination, suggesting that the formula is very useful for prediction of the prognosis. In a genetic analysis of HTLV-I, the ratio of non-synonymous change to synonymous change (dN/dS ratio) of HTLV-I gene was lower in HAM patients than in HTLV-I carriers, implying that viral replication is more effectively inhibited in HAM patients than in the carriers. Moreover, HAM patients with HLA-A^*02 had lower dN/dS ratio than those without HLA-A^*02, suggesting that HL-A^*02 has an inhibitory effect on viral replication. Additionally, an analysis of dN/dS ratio, cytotoxic T lymphocytes(CTL) epitopes and frequency of mutant virus demonstrated that CTL had antiviral pressure in vivo, however, a mutant virus did not predominate. Further studies are needed to establish a more effective therapy for HAM patients.
|
