초록 ▼

1. 노인 암의 전신 면역학적 및 조직 생물면역학적 마커의 발굴과 유전적 및 후성 유전학적 기전 연구
• 노령 암 동물 모델을 이용한 노인암의 생물학적 특성 규명
• High-throughput 기법을 이용한 노인 소화기암의 면역 특이 유전자 발굴
• 노인 소화기암의 면역 특이 유전자의 메틸화 연구
• 노인 소화기암의 면역 프로파일을 이용한 면역학 평가의 임상적으로 규명
2. 고령층의 선천성 면역에 관여하는 골수계 세포의 기능 회복 인자 발굴 연구
• 노화에 따른 대식세포 탐식기능

1. 노인 암의 전신 면역학적 및 조직 생물면역학적 마커의 발굴과 유전적 및 후성 유전학적 기전 연구
• 노령 암 동물 모델을 이용한 노인암의 생물학적 특성 규명
• High-throughput 기법을 이용한 노인 소화기암의 면역 특이 유전자 발굴
• 노인 소화기암의 면역 특이 유전자의 메틸화 연구
• 노인 소화기암의 면역 프로파일을 이용한 면역학 평가의 임상적으로 규명
2. 고령층의 선천성 면역에 관여하는 골수계 세포의 기능 회복 인자 발굴 연구
• 노화에 따른 대식세포 탐식기능 조절 물질 발굴 및 염증반응 조절 기전연구
• 노화된 수지상 세포의 활성 평가 시스템 구축 및 기전 규명
• 골수계 세포의 노화에 따른 세포의 분자적 변화 관찰 및 기전 규명
• 노화 및 암발생에 따른 엑소좀과 골수유래억제세포의 변화
3. 고령층의 염증성 T 세포 연구를 통한 T 세포 항상성 조절 연구
• 노인 천식 환자의 면역력 데이터베이스 구축 및 T 세포 아형 분석.
• SAA3와 CEA, sFRP1 등을 이용한 염증성 세포의 분화 조절.
• 노화 유래 기능 저하 CD8 T 세포가 노화 개체 내에서 IL-10의 축적에 기여함.
• Osteopontin을 중화하는 항체 및 GITR 자극 항체를 이용한 항암 치료의 효율 증진.
4. 고령층의 면역력 약화를 유발하는 환경 위험인자의 탐색 및 회복 기술 개발
• 고령층 환경 위험 인자 2 종 이상 발굴 및 기전 규명.
• cPLA₂ 억제 효능 물질 1 종 및 IL-1β 신호전달 억제 효능 물질 3 종 발굴.
• 노인성 질환 모델에서 회복 방안 모색함.

(출처 : 보고서 요약서 3p)

Abstract ▼

III. RESULTS

1. Study on identification of molecular characteristics of geriatric cancer through high-throughput genomics and epigenetics technology
• As the animal model ages, tumorogenicity increases
• Aged model shows tendency of decreased T naive portion and increased T eff port

III. RESULTS

1. Study on identification of molecular characteristics of geriatric cancer through high-throughput genomics and epigenetics technology
• As the animal model ages, tumorogenicity increases
• Aged model shows tendency of decreased T naive portion and increased T eff portion
• CD44+PD1+/CD44+TIM3+ increases as aging, and high in TIL
• Oxaliplatin's tumor suppression ability decreases as the model ages
• According to ROC analyzing, ENOSF1, an antisense gene in TS, is expressed at low level in geriatric gastrointestinal cancer patients over 70
• Among methylation confirmed genes, p16, p14, MINT1, MINT2, MINT31, and MLH1, only MINT2 gene exhibits increased methylation (20.5%) in patients over age of 65 when compared to patients age <65 (11.1%)
• Expression in normal colon tissue is criticaly higher than in a tumor tissue. In normal colon tissue, KLF4 expression is higher in younger age. In tumor tissue, as KLF4 expression is low, the survival of patients is better. The possibility of using KLF4, the immune specific gene, as a prognostic marker is confirmed
• Anti-cancer drug targeting geriatric colorectal cancer stage 2 is not effective, but, at stage 3, it is effective
• Immunological risk profile's parenchyma cell measurement condition and clinical procedure are established. Throughout this, investigate the difference among immune senescence, immune regulation, bone marrow reservoir, and cancer stem cell antigen load
• Confirm expression variation of IL-2, IL-6, and IL-8 depending age
• Depending on age, antibody production against bacteria decreases
• Throughout comparison between dead patients and recovered patients, antibody production against bacteria in dead patients decreases, and CD4/CD8 T-cell ration is significantly low.
• This phenomenon is expected to be used as a prognostic marker for a future patient in a clinic

2. Study on the discovery of functional recovery factors of myeloid lineage cells involved in innate immunity in the elderly
• We examined the phagocytic functions of macrophages and found out chemicals that effectively modulate the phagocytic function of aged macrophages.
• C10 and its derivatives decreased the Dectin-1 levels. These compounds inhibited the translocation of PU.1, transcription factor of Dectin-1, and modultae the expression of Dectin-1. Decreased Dectin-1 suppressed its dwon-stream signalling pathway and as a result, it diminished inflammation responses of macropahges.
• Extracts of E. kansui Root induced regulatory macrophage subtype. E. kansui induced the production of anti-inflammatory cytokine IL-10 and SPHK1, LIGHT the bio-marker of regulatory macrophge. Conversely, E. kansui inhibited the production of IL-6 and TNF-α, inflammatory cytokine. These effects of E. kansui occurred by up-regulation of phsphorylation of ERK and JNK.
• In addition, we set-up the system for evaluating the activities of aged dendritic cells & Identifying its mechanisms. The expression of DC-SIGN was decreased in elderly. We performed the screening using Luciferase Reporter assay to discover the natural products which modulate the expression of DC-SIGN.
• D.herba modulated the expression levels of Dectin-1 through the transcription factor PU.1. Upregulated Dectin-1 expression promote the phagocytic function and reversed immune responses.
• Age-associated changes in myeloid cells at cellular and molecular levels. The expressions of myelogenic miRNAs such as miR-155, miR-223, miR-146a, miR-146b, miR-132, miR-142-5p, and miR-142-3p were increased in aged bone marrow derived dendritic cells (BMDC) under normal and activated conditions.
• The expressions of IRAK1 and TRAF6, the targets of miR-146a, and DC-SIGN, a target of miR-155 were diminished while miR-146a and miR-155 were augmented during aging.
• The production of pro-inflammatory cytokines, which is mediated by the activation of NF-kB pathway via IRAK1 and TRAF6, was greatly reduced in aged BMDC.
• Tested aminosulfonylarylisoxazole compounds exhibited specificity for miR-31 over other six miRNAs including miR-15a, miR-16, miR-21, miR-92a-1, miR-146a, and miR-155, along with an increase of target genes of miR-31.
• There was a significant increase in the amount of exosome per unit serum volume in normal group with age, while there was no change in the amount of exosome in cancer patients with age.
• Chemotherapy decreased the level of TGF-beta and IL-10 within exosomes in young cancer patients, while chemotherapy did not cause any change in TGF-beta and IL-10 in old cancer patients.
• We identified several miRNA which is modulated on tumor associated MDSC and it is analyzed by microarray. The result confirmed that target gene expression and miRNA expression appeared conversely.

3. Studies of inflammatory T cell and T cell homeostasis in the elderly
• The elderly had more Foxp3⁺ Treg cells the percentage of non-immunosuppressive Foxp⁺ non-Treg cells in the elderly increased by a great degree.
• Elderly non-atopic asthma patients had more Treg cells screting IFN-γ and IL-13 than adult patients.
• SAA3 (Serum amyloid A3) was increased in monocytic MDSCs of tumor-bearing mice. SAA3 enhanced immuno-suppressive functions of MDSCs by activating STAT3 and TLR2-mediated secreting IL-6 and TNF-α.
• NK cells were differentiated into MDSCs by various cytokines in a tumor microenvironment, which was found to be restrained by IL-2.
• CEA (Carcinoembryonic antigen) was found to regulate the activation and proliferation of human CD4 T cells.
• Among regulatory T cell subsets of elderly asthma patients, non-Treg increased while the functions of resting Treg and activated Treg diminished. It is therefore considered to be less effective in regulating immune responses.
• ICOS, GITR, CD69 and CD25 were expressed more in aged murine T cells than young T cells.
• GITR stimulation decreased the differentiation into Th1, Th17 and Treg cells, while selectively increasing the differentiation into Th9 cells. The increase in the differentiation into Th9 cells by GITR stimulation also occurred in tumor-bearing mice, and ultimately expedited anti-tumor effects.
• Age-associated-exhausted CD8 T cells that co-express Tim-3 and PD-1 contribute ro accumulation of IL-10 in aged individuals by promoting normal CD8 T cells to produce IL-10.
• The efficiency of anti-tumor effects was improved by neutralizing osteopontin, which comtributes to extramedullary myelopoiesis in tumor-bearing mice.

4. Search and recovery technical development of environmental risk factors that cause immunosenescence of aged people
• Found 2 environmental risk factors (paraquat dichloride from 9 pesticides; sodium arsenite from 7 heavy metals) in old mouse model and quantified those amount.
• Pyrethroid infecticide, permethrin and cypermethrin increase the production amount of inflammatory cytokines such as IL-1βand IL-6.
• Cigarette smoke extract decrease the amount of glutathione which is an intrinsic antioxidant and exposure to cigarette smoke increase the production amount of inflammatory cytokines leading to immune cell infiltration into lung tissue.
• Because chronic inflammatory reaction is an characteristic of the elderly immunity, the exposure to arsenite, permethrin, cypermethrin and cigarette smoke should be cautious in the elderly.
• The decrease of T cell proliferation and NK cell activation through exposure to paraquat may be due to insufficient amount of zinc.
• After screening domestic naturally growing plant extracts from up to 1600 species, discovered 3 species which has an inhibitory efficacy against signal transduction pathway to activate IL-1β which is a highly sensitive inflammatory cytokine in the elderly: Ambrosia artemisiifolia var. elatior extract, Robinia pseudo-accacia extract and Michelia compressa extract.
• Confirmed the effectiveness of PACAP-38 in NK cell mediated target cancer cell cytotoxicity enhancement, so it can be used for the therapeutic strategy to treat lung cancer in the elderly.

(출처 : SUMMARY 11p)

목차 Contents

• 표지 ... 1
• 제 출 문 ... 2
• 보고서 요약서 ... 3
• 요 약 문 ... 4
• SUMMARY ... 11
• CONTENTS ... 16
• 목차 ... 17
• 제 1 장 연구개발과제의 개요 ... 18
• 제 1 절 연구개발의 목적 ... 18
• 제 2 절 연차별 연구개발의 목표 및 내용 ... 19
• 제 3 절 연구개발의 필요성 ... 25
• 제 2 장 국내외 기술개발 현황 ... 29
• 제 1 절 연구개발대상 기술의 국내․외 현황 ... 29
• 제 2 절 지금까지의 연구개발실적 ... 31
• 제 3 절 연구결과가 국내․외 기술개발현황에서 차지하는 위치 ... 33
• 제 3 장 연구개발수행 내용 및 결과 ... 34
• 제 1 세부과제 및 위탁과제 ... 34
• 제 2 세부과제 ... 60
• 제 3 세부과제 및 위탁과제 ... 81
• 제 4 세부과제 ... 102
• 제 4 장 목표 달성도 및 관련분야에의 기여도 ... 129
• 제 5 장 연구개발결과의 활용계획 ... 143
• 제 1 절 연구개발결과의 활용방안 ... 143
• 제 2 절 연구개발결과의 기대성과 ... 144
• 제 6 장 연구개발과정에서 수집한 해외과학기술정보 ... 147
• 제 7 장 참고문헌 ... 151
• 끝페이지 ... 174