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방사선에 의한 신경줄기세포 손상 및 인지 장애 경감 물질 검색
Investigation of protective materials on radiation-induced neural stem cell damage and cognitive deficits

  • 사업명

    원자력연구기반확충사업

  • 과제명

    방사선에 의한 신경줄기세포 손상 및 인지 장애 경감 물질 검색

  • 주관연구기관

    전남대학교
    Chonnam National University

  • 연구책임자

    김성호

  • 참여연구자

    문창종   김희수   김중선   류재선   양미영   송명섭   서흥식   손영훈   정지선   장효선  

  • 보고서유형

    최종보고서

  • 발행국가

    대한민국

  • 언어

    한국어

  • 발행년월

    2010-05

  • 과제시작년도

    2008

  • 주관부처

    교육과학기술부

  • 사업 관리 기관

    한국과학재단
    Korea Science and Engineering Foundtion

  • 등록번호

    TRKO201000014084

  • 과제고유번호

    1345075085

  • 키워드

    방사선.신경줄기세포.인지장애.경감물질.행동학적 검사.퇴행성뇌질환.Radiation.Neural stem cell.Cognitive deficits.Protective materials.Behavior test.Neurodegenerative disorder.

  • DB 구축일자

    2013-04-18

  • 초록 


    The purpose of this study is to investigate the underlying mechanism of clinical cognitive impairment due to irradiation via cell...

    The purpose of this study is to investigate the underlying mechanism of clinical cognitive impairment due to irradiation via cell biological (studying the change of neurogenesis and neuroplasticity in hippocampal neurons) and animal behavior test, and finally acquire fundamental data for development of protective materials.
    <1st year>
    $\bullet$ Evaluate the effect of radiation on histological and behavior changes
    - Test the histological changes of neurogenesis-related cell death after irradiation
    - Test the hippocampal-dependent learning and memory behavior tasks following irradiation
    $\bullet$ Evaluate the effect of candidate materials (2 materials) on radiation-induced histological and behavior changes
    - Test the effect of candidate materials on histological changes of neurogenesis-related cell death after irradiation
    - Test the effect of candidate materials on hippocampal-dependent learning and memory behavior tasks following irradiation
    <2nd year>
    $\bullet$ Evaluate the effect of candidate materials (2 materials) on radiation-induced histological and behavior changes
    - Test the effect of candidate materials on histological changes of neurogenesis-related cell death after irradiation
    - Test the effect of candidate materials on hippocampal-dependent learning and memory behavior tasks following irradiation
    $\bullet$ Establishment the experimental model of evaluation the change of radiation-induced histological and behavior changes
    $\bullet$ Acquire fundamental data for development of protective materials.
    To observe the effect of HemoHIM, amifostine, green tea, epigallocatechin-3-gallate, ginseng, diethyldithiocarbamate on the recognition memory defect in ARS, the experimental groups of mice (n = 7 in each group) were sham irradiated (0 Gy; control) or were whole-body irradiated with 2 Gy $\;^{60}Co$ gamma-rays using a Gamma-cell Elan 3000 (Nordion International, Ottawa, ON, Canada) at a dose-rate of 3.1 Gy/min. An object recognition memory training was then performed 24 h post-irradiation. To discern the effect of amifostine on apoptotic cell death and the inhibition of neurogenesis in the adult hippocampus with ARS, mice (n = 4 mice/group) were sham irradiated (control) or whole-body irradiated with 0.5 or 2 Gy $\;^{60}Co$ gamma-rays. The mice were sacrificed 12 h after irradiation, and the brain were then dissected from each mouse. An object recognition memory test representing a hippocampus-dependent learning paradigm was performed. Briefly, the mice were first habituated in a 41.6 cm long x 27.6 cm wide x 17.8 cm high training/testing chamber for 24 h. Objects for recognition to be
    discriminated, which were made from plastic, had three different shapes: cubes, pyramids and cylinders that were 3.5 cm high and they could not be displaced by the mice. During training, two randomly objects were presented to each mouse for 15 min. Twenty-four hours after training, another pair of objects that included one of the previously-presented objects and the remaining object that had not been presented was presented to the same mouse. The interactionsof the mouse with each object, including approaches and sniffing, were scored. The percentage of preference was defined as the
    "number of interactions for a specific object" divided by the "total number of interactions for both objects". The level of DNA fragmentation was detected by in situ nick end-labeling (terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end-labeling; TUNEL) using an $ApopTag^®$ in situ apoptosis detection kit (Intergen, Purchase, NY, USA) according to the manufacturer’s instructions. For immunohistochemistry, five micron-thick coronal sections of paraffin wax-embedded brain were deparaffinized and allowed to react with immunohistochemical markers for neurogenesis including a 1:500 dilution of monoclonal rabbit anti-Ki-67 antibody (DRM004; Acris Antibodies GmbH, Hiddenhausen, Germany) and a 1:400 dilution of polyclonal rabbit anti-DCX antibody (Cell Signaling Technology, Beverly, MA, USA), as described previously. The immunoreactions were visualized using avidin-biotin peroxidase complexes (Elite kit; Vector, Burlingame, CA, USA), and each peroxidase reaction was developed using a diaminobenzidine substrate kit (Vector). The number of cells showing the specific characteristics of proliferating cells (immunopositive for Ki-67) and immature progenitor cells (immunopositive for DCX) in the hippocampus was scored by an observer blinded to the identity of the sample using a histomorphometric approach. The brain from each mouse was sampled approximately 2.12 mm behind the bregma. A standardized counting area containing 5 $\mu$m-thick coronal sections in a one-in-ten series of sections representing the rostral/mid-hippocampus was used. For each mouse, three non-overlapping sections were analyzed, one each from the three regions of the hippocampus approximately 50 $\mu$m apart. All positively immunolabeled cells within the SGZ of the supra- and infra-pyrimidal blades of the DG were quantified. The number of immunopositive cells was determined from the values obtained from each DG in the three brain sections. The mean number of immunopositive cells in the three sections of each mouse was taken as n = 1. HemoHIM, amifostine, ginseng and diethyldithiocarbamate treatment prior to irradiation significantly attenuated the recognition memory defect in ARS, and markedly blocked the apoptotic death and decrease of Ki-67- and DCX-positive cells in ARS. HemoHIM, amifostine, ginseng and diethyldithiocarbamate may attenuate recognition memory defect in a relatively low-dose exposure of ARS in adult mice, possibly by inhibiting a detrimental effect of irradiation on hippocampal neurogenesis.


    방사선 조사에 의한 뇌의 신경줄기세포 손상과 이와 관련된 인지(학습 및 기억) 장애의 정도를 파악하고 후보물질의 장애 경감효과를 조직형태학적 및 기능행동학적으로 검색하여 장애 경감제품 개발을 위한 자료를 획득하고자 하였다. 연차별 ...

    방사선 조사에 의한 뇌의 신경줄기세포 손상과 이와 관련된 인지(학습 및 기억) 장애의 정도를 파악하고 후보물질의 장애 경감효과를 조직형태학적 및 기능행동학적으로 검색하여 장애 경감제품 개발을 위한 자료를 획득하고자 하였다. 연차별 연구내용 및 범위는 아래와 같다.
    제1차년도 : 저선량 및 고선량 방사선에 의한 신경줄기세포 변화를 조직형태학적 및 기능행 동학적으로 평가하고 손상 경감 후보물질(2종 : 헤모힘, WR-2721 (amifostine) )의 효과를 평가
    $\bullet$저선량 및 고선량 방사선에 의한 신경줄기세포 변화의 조직형태학적 및 기능행동학적평가
    -인지 관련 신경세포 apoptosis 발생, 내인성 증식인자 및 미성숙 신경줄기세포 변화평가
    -일반 운동성$\cdot$행동 검사 및 인지(학습$\cdot$기억) 변화 평가
    $\bullet$$\cdot$고선량 방사선에 의한 신경줄기세포 손상 경감 후보물질의 효과 평가(2종)
    -인지 관련 신경세포 apoptosis 발생 제어 효과 평가
    -인지 관련 신경세포의 내인성 증식인자 및 미성숙 신경줄기세포 변화 제어 효과 평가
    -일반 운동성$\cdot$행동 검사 및 인지(학습$\cdot$기억) 장애 경감 효과 평가
    제2차년도 : 저$\cdot$고선량 방사선에 의한 신경줄기세포 손상 경감 후보물질(4종 : 녹차, epigall ocatechin-3-gallate (EGCG), 인삼, Diethyldithiocarbamate (DDC) )의 효과 평가 및 장애 경감 물질 도출
    $\bullet$ 저선량 및 고선량 방사선에 의한 신경줄기세포 손상 경감 후보물질(4종)의 조직형태학적 효과 평가
    -인지 관련 신경세포 apoptosis 발생 제어 효과 평가
    -인지 관련 신경세포의 내인성 증식인자 및 미성숙 신경줄기세포 변화 제어 효과 평가
    $\bullet$ 방사선에 의한 신경줄기세포 손상 경감 후보물질(4종)의 기능행동학적 효과 평가
    -일반 운동성$\cdot$행동 검사 및 인지(학습$\cdot$기억) 장애 경감 효과 평가


  • 목차(Contents) 

    1. 표지...1
    2. 제출문...3
    3. 보고서 초록...4
    4. 요약문...5
    5. SUMMARY...10
    6. 목차...14
    7. 제1장 연구개발과제의 개요...15
    8. 제2장 국내ㆍ외 기술개발 현황...16
    9. 제3장 연구개발 수행내용 및 결과...21
    10. 제1절 연구...
    1. 표지...1
    2. 제출문...3
    3. 보고서 초록...4
    4. 요약문...5
    5. SUMMARY...10
    6. 목차...14
    7. 제1장 연구개발과제의 개요...15
    8. 제2장 국내ㆍ외 기술개발 현황...16
    9. 제3장 연구개발 수행내용 및 결과...21
    10. 제1절 연구개발 수행내용...21
    11. 제2절 연구결과 및 고찰...27
    12. 제4장 목표 달성도 및 관련 분야에의 기여도...57
    13. 제1절 연구개발 목표의 달성도...57
    14. 제2절 관련 분야에의 기여도...58
    15. 제5장 연구개발결과의 활용계획...60
    16. 제6장 연구개발과정에서 수집한 해외 과학기술정보...63
    17. 제7장 참고문헌...65
  • 참고문헌

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