초록 ▼

본 연구에서 저자들은 근위축성측삭경화증 동물 모델을 이용한 신약개발 시스템을 확립하고 SOD1 돌연변이 운동신경 세포 모델에서 효과를 확인한 신약후보물질인 pyruvate, UDCA, erythropoietin therapy의 효과를 확인하여 임상시험으로 들어가기 위한 자료를 모으고, 근위축성측삭경화증의 병리기전에 대한 이해를 돕고자 하였다.
저자들은 UDCA, pyruvate, erythropoietin, testosterone이 in vitro와 in vivo ALS model에 신경세포 보호효과가 있음을 보였으며 향후 A

본 연구에서 저자들은 근위축성측삭경화증 동물 모델을 이용한 신약개발 시스템을 확립하고 SOD1 돌연변이 운동신경 세포 모델에서 효과를 확인한 신약후보물질인 pyruvate, UDCA, erythropoietin therapy의 효과를 확인하여 임상시험으로 들어가기 위한 자료를 모으고, 근위축성측삭경화증의 병리기전에 대한 이해를 돕고자 하였다.
저자들은 UDCA, pyruvate, erythropoietin, testosterone이 in vitro와 in vivo ALS model에 신경세포 보호효과가 있음을 보였으며 향후 ALS환자에서의 신약 개발의 가능성을 제시하였다.

Abstract ▼

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that produces selective motor neuron death. Currently no effective pharmacological treatment is available for ALS. In this study, we investigated the neuroprotective effects of UDCA, pyruvate and erythropoietin in ALS mod

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that produces selective motor neuron death. Currently no effective pharmacological treatment is available for ALS. In this study, we investigated the neuroprotective effects of UDCA, pyruvate and erythropoietin in ALS model.
TUDCA showd the improvement in survival of A4V mutant mouse which was suppressed by W13, LY294002, and PD 058509. And TUDCA can prevent apoptosis by W13, LY294002, and PD 058509, can also suppress the expression of Bax and cleavage of PARP. We concluded that TUDCA decreased the degeneration of the motor neuron by activation of survival signal pathway or prevention of apoptosis.
We treated G93A SOD1 transgenic mice with pyruvate (from 70 days of age, i.p., at 1000 mg/kg/week), and found that it prolonged average lifespan by 12.3 days (10.5%), slowed disease progression, and improved motor performance, but did not delay disease onset. Pyruvate treatment was also associated with reduced nitrotyrosine immunoreactivity, gliosis, and increased Bcl-2 expression in the spinal cords of G93A SOD1 transgenic mice.
We also revealed that erythropoietin can have neuroprotective effect in mutant SOD1 G93A ALS model and this effect is most prominant againt the GSNO induced cytotoxicity. This results favor the previous studis that erythropoietin can act via MAPK/P13K pathway. We also proved that erythropoietin can have anti-apoptotic effect.
We also perform the study to show that testosterone can delay the disease precess in ALS. S-nitrosoglutathione showed significant neurotoxic effect in all three cell lines. Percentage of cell death was somewhat different in each cell line. 1 nM testosterone showed neuroprotective effect in G93A and wild-type cell line. In A4V cell line, testosterone did not showed neuroprotective effect. The neuroprotective effect of testosterone was reversed by 20 μM flutamide.
In summary, we revealed that UDCA, pyruvate erythropoietin and testosterone can have neuroprotective effect in the ALS model and showed the possibility of new treatment modality for ALS patients.

목차 Contents

• 표지...1
• 2. 제출문...2
• 3. 보고서 요약서...3
• 4. 요약문(한글)...4
• 5. 요약문(영문)...5
• 6. 연구 성과 실적 및 향후 계획...6
• 7. 참여연구원 현황표...26
• II. 총괄연구과제 연구결과...27
• 1. 연구개발과제의 배경 및 필요성...28
• 2. 국내외 기술개발 현황...29
• 3. 연구개발과제의 추진체계...34
• 4. 연구개발수행 내용 및 결과...35
• 1. ALS and erythropoietin...36
• 2. ALS and UCDA...46
• 3. Pytuvate and ALS...50
• 4. Testosterone and ALS...54
• 5. 결론...62
• 5. 목표달성도 및 관련분야 기여도...63
• 5.1. 총괄연구개발과제의 목표달성도...63
• 5.2. 관련분야 기여도...65
• 6. 향후 연구성과 추진 계획(※해당되는 경우만 작성)...65
• 7. 연구개발결과의 파급효과...65
• 7.1. 기술적 파급효과...65
• 7.2. 경제.산업적 파급효과...65
• 7.3. 사회적 파급효과...65
• 8. 연구개발결과의 활용계획...66
• 8.1. 연구개발결과의 활용계획 및 추가연구의 필요성...66
• 8.2. 사업화(기업화) 목표 달성도 및 계획(※해당과제만 작성함)...66
• 8.3. 사업화 수준(계획 및 완료 포함)(※해당과제만 작성함)...66
• 9. 연구개발과정에서 수집한 해외과학기술정보...66
• 1. 자체평가의견서...67
• 2. 연구성과 실적 증빙자료...71