초록 ▼

본 연구에서는 인체의 발생과정 중 Sonic Hedgehog (Shh) 신호체계의 이상으로 일어나는 질환들의 원인 유전자들을 체계적으로 분석함으로써 분자조절기전의 종합적 이해를 통한 선천성 발생장애질환을 이미 동물실험에서 그 증상들이 확인 된 Cdo유전자를 중심으로 연구하였음. 이러한 연구는 심각한 뇌의 기형을 동반하는 통앞뇌증 (Holoprosencephaly)과 안검홍채맥락막선천적결손증 (coloboma)을 비롯한 선천성 희귀질환을 사전에 진단 및 예방하는데 기여할 것으로 사료됨.
1. Cdo Knockout MEF (Mo

본 연구에서는 인체의 발생과정 중 Sonic Hedgehog (Shh) 신호체계의 이상으로 일어나는 질환들의 원인 유전자들을 체계적으로 분석함으로써 분자조절기전의 종합적 이해를 통한 선천성 발생장애질환을 이미 동물실험에서 그 증상들이 확인 된 Cdo유전자를 중심으로 연구하였음. 이러한 연구는 심각한 뇌의 기형을 동반하는 통앞뇌증 (Holoprosencephaly)과 안검홍채맥락막선천적결손증 (coloboma)을 비롯한 선천성 희귀질환을 사전에 진단 및 예방하는데 기여할 것으로 사료됨.
1. Cdo Knockout MEF (Mouse Embryonic Fibroblast)를 이용하여 통앞뇌증 환자에게서 나타나는 Cdo 돌연변이들의 Shh 신호체계에서의 기능적 역할분석.
2. Cdo knockout mice의 눈 발생과정에서의 특이적인 phenotype 분석 및 시신경과 수정체 분화조절인자 규명.

Abstract ▼

I. Purposes of the proposed Research
In this proposed study, we have investigated the molecular regulatory mechanisms by which Cdo contributes human birth defects caused by the defective Sonic Hedgehog (Shh) signaling pathways by utilizing Cdo knockout mouse models. The results from this proposal

I. Purposes of the proposed Research
In this proposed study, we have investigated the molecular regulatory mechanisms by which Cdo contributes human birth defects caused by the defective Sonic Hedgehog (Shh) signaling pathways by utilizing Cdo knockout mouse models. The results from this proposal is expected to contribute to diagnosis and prevention of human birth defects, such as holoprosencephaly and coloboma which have been associated with mutations in the Shh signaling components.

II. Contents of the proposed Research
Shh signaling is involved in regulation of fate determination, differentiation and proliferation of multiple progenitor cells during embryonic development and deregulation of the Shh signaling activity has been linked to human birth defects as well as several cancers. Thus understanding the molecular mechanisms of the Shh signaling pathway is important for prevention and intervention of these diseases. Cdo (CAM-related, Downregulated by Oncogene) has been cloned by PI and recently we and others have shown that Cdo functions as a coreceptor for the Shh signaling pathway by the direct binding to Shh and its primary receptor, Patched1. Cdo depletion in mice causes phenotypes associated with a human birth defect called holoprosencephaly. In this proposal, We have focuses on two specific aims. 1) the functional studies of mutations identified in the human Cdo gene of holoprosencephaly patients. 2) Analysis of eye defects (especially Coloboma and microphthalima) of Cdo knockout mice and defects of Shh signaling in early eye development of such animals.

III. Outcomes of the proposed Research
1. Functional analysis of mutations found in the human Cdo gene from holoprosencphaly patients.
- Analysis of effects of Cdo mutations on the Shh signaling activity
- Analysis of expression of the Shh signaling components, Shh, Gli-1, Patched1
- Analysis of interactions between Cdo, Boc, Shh and Patched-1
- Analysis of Cdo and Gas1 by utilizing Cdo deletion mutants
2. Analysis of Cdo knockout phenotypes
- Analysis of Cdo knockout phnotypes during eye development
- Analysis of expression of Cdo mRNA during eye development
- Analysis of cell death during early eye development from E11.5 to E13.5
- Analysis of expression of marker genes (Pax6, Tbx5, Pax2 and Vax2) during specification of retina specification

IV. Expected Contribution
- Development of a prognosis marker for genetic disorders via understanding molecular mechanisms of the Shh signaling pathway such as holoprosencephaly and coloboma
- Identification of molecular mechanisms of the Shh signaling pathway thereby publishing the outcome in a high profile journal
- Acquiring internationally competitive research techniques by using genetically modified mouse models.
- Establishment of techniques to induce an efficient differentiation of stem cells and education of researchers in the field of specification and differentiation of stem cells.

목차 Contents

• 겉표지 (앞면) ...1
• 제출문 ...3
• 보고서 요약서 ...4
• 요약문 (한글) ...5
• 요약문 (영문) ...6
• 연구 성과 실적 및 향후 계획 ...8
• 참여연구원 현황표 ...12
• II. 총괄연구과제 연구결과 ...13
• 1. 연구개발과제의 배경 및 필요성 ...14
• 2. 국내외 기술개발 현황 ...16
• 3. 연구개발과제의 추진체계 ...17
• 4. 연구개발수행 내용 및 결과 ...18
• 5. 목표달성도 및 관련분야 기여도 ...26
• 6. 향후 연구성과 추진 계획 ...27
• 7. 연구개발결과의 파급효과 ...27
• 8. 연구개발결과의 활용계획 ...28
• 9. 연구개발과정에서 수집한 해외과학기술정보 ...28
• 10. 참고문헌 ...28
• IV. 첨부서류 ...30
• ○. 실적증빙자료 및 첨부서류 목차 ...31
• 1. 자체평가의견서 ...32
• 2. 실적 증빙자료 ...36