초록 ▼

루푸스 신염은 정확한 발병기전이 잘 알려져 있지 않은 대표적인 난치성 자가면역질환임. 본 연구는 신약후보물질인 HL-156의 바이오에너제틱스 조절을 통한 면역세포 활성조절 가능성을 규명하는 연구임.
세포실험에서 HL-156 처리시 CD4+, CD8+ T cell의 증식 저해를 확인하였고, T cell subset에서 HL-156A가 T cell 활성 조절 능력이 있음을 확인함. 이러한 효과는 mitochondria activation의 억제와 관련되어 있음을 확인함. 동물실험에서는 루푸스 신염모델인 NZBW/F1 mice를 이

루푸스 신염은 정확한 발병기전이 잘 알려져 있지 않은 대표적인 난치성 자가면역질환임. 본 연구는 신약후보물질인 HL-156의 바이오에너제틱스 조절을 통한 면역세포 활성조절 가능성을 규명하는 연구임.
세포실험에서 HL-156 처리시 CD4+, CD8+ T cell의 증식 저해를 확인하였고, T cell subset에서 HL-156A가 T cell 활성 조절 능력이 있음을 확인함. 이러한 효과는 mitochondria activation의 억제와 관련되어 있음을 확인함. 동물실험에서는 루푸스 신염모델인 NZBW/F1 mice를 이용하여 HL-156 치료시 생존률 증가 및 단백뇨 감소 효과를 확인함.
본 연구는 루푸스 신염의 발생과정을 이해하는데 새로운 기전을 제시하였으며, 이를 통해서 T 세포 면역활성 및 조절에 있어 에너지 대사의 역할의 중요성을 확인함. 이는 면역세포 대사 조절을 통한 타 질환의 치료효과 연구에 대해서도 파급효과가 있을 것으로 기대됨.

(출처 : 요약서 3p)

Abstract ▼

□ Purpose&Contents
Lupus nephritis is a autoimmune disease with the abnormal T cell activation and is still intractable with current medical technology. Sudden changes in intracellular energy metabolism is induced during T cell activation in SLE patients. Recently several studies have performed t

□ Purpose&Contents
Lupus nephritis is a autoimmune disease with the abnormal T cell activation and is still intractable with current medical technology. Sudden changes in intracellular energy metabolism is induced during T cell activation in SLE patients. Recently several studies have performed to suppress the activation of T cells by controlling the changes in the bioenergetics of T cell. The final goal is to investigate a new drug therapies by drug repositioning for lupus nephritis using bioenergetics controlling drugs. We uses HL-156A substance which was originally developed for anti-cancer agent.
1. In vitro T cell bioenergetics evaluation
2. In vivo T cell bioenergetics evaluation
3.T cell bioenergetics evaluation in lupus nephritis animal model
4. Evaluation of drug candidates using drug repositioning.

□ Results
1. We confirmed that an AMPK activator HL-156A inhibits CD4 + and CD8 + T cell proliferation at concentrations of 5uM, 15uM without cytotoxicity.
2. We confirmed a synergy in the combination treatment with rapamycin, 2DG and PI3K inhibitor that isolate HL156A treatment.
3. CD4 + and CD8 + T cell of PBMC from the mouse 8 days after LCMV infection, CD127lo CD62Llo effector T cells population was higher. Characteristically, CD127lo KLRG1hi SLEC (short-lived effector T cells) are increased in the CD8 + T cells. Expression of CD62L and CD127 in CD8+ T cell was increasing while the expression of KLRG1 was decreasing. CD127hi CD62Llo effector memory T cells were increased in the rapamycin-treated group and rapamycin HL156A cotreated group than the control group. these changes were more prominent in the antigen specific GP33 + CD8 + T cell. Above findings showed the regularoty effect of HL-156A on T cells in vivo.
4. The effect of mitochondria inhibitor (HL-156A) on the development of lupus nephritis model was confirmed using NZBW / F1 mouse.
5. We confirmed that HL-156A reduced proteinuria in lupus nephritis.
6. We confirmed that HL-156A was effective in relieving weight loss in lupus nephritis.
7. We confirmed that HL-156A has an effect of increasing survival rate in lupus nephritis.
8. We confirmed the tendency of T-cell activation to increase as lupus nephritis symptoms became more severe.
9. HL-156A has been shown to reduce effector CD127-CD8 + T cells.
10. The survival and proliferation of CD4 + effector T cells after HL-156 treatment was significantly decreased compared to that of regulatory T cells.
11. The expression of PD-1 and OX40 in both CD4 + effector T cells and regulatory T cells was significantly reduced in a dose-dependent manner.
12. T cell mitochondrial activation was also inhibited from HL-156 in a dose-dependent manner.

□ Expected Contribution
1. Establish first-in class innovative new drug targets
- Immunomodulation through T cell energy metabolism has not been yet tried worldwide, which has the possibility of being an innovatice new drug target First in Class
2. Excellency in Translational research in lupus nephritis
- Promotion of research competitiveness in the field of T cell energy metabolism on lupus nephritis pathogenesis.
3. Drug development by drug repositioning technique on pharmaceutical industry.
- Drug repositioning will provide better chance of success with low budget by recycling previous data.

(출처 : SUMMARY 5p)

목차 Contents

• 표지 ... 1
• 제출문 ... 2
• 보고서 요약서 ... 3
• 국문 요약문 ... 4
• SUMMARY ... 5
• 목차 ... 6
• 1. 연구개발과제의 개요 ... 7
• 1-1. 연구개발 목적 ... 7
• 1-2. 연구개발의 필요성 ... 7
• 1-3. 연구개발 범위 ... 7
• 2. 국내외 기술개발 현황 ... 8
• 3. 연구수행 내용 및 결과 ... 8
• 1-1. 정량적 연구성과 ... 8
• 1-2. 정성적 연구성과 ... 9
• 4. 목표달성도 및 관련분야 기여도 ... 32
• 4-1. 목표달성도 ... 32
• 4-2. 관련분야 기여도 ... 32
• 5. 연구결과의 활용계획 ... 32
• 6. 연구과정에서 수집한 해외과학기술정보 ... 33
• 7. 연구개발성과의 보안등급 ... 33
• 8. 국가과학기술종합정보시스템에 등록한 연구시설·장비 현황 ... 33
• 9. 연구개발과제 수행에 따른 연구실 등의 안전조치 이행실적 ... 34
• 10. 연구개발과제의 대표적 연구실적 ... 34
• 11. 기타사항 ... 34
• 12. 참고문헌 ... 35
• 별첨4. 실적 증빙자료 ... 36
• 별첨5. 기타 첨부서류 ... 40
• 끝페이지 ... 47