| Project/Area Number |
18K19424
|
|---|
| Research Category |
Grant-in-Aid for Challenging Research (Exploratory)
|
| Allocation Type | Multi-year Fund |
|---|
| Review Section |
Medium-sized Section 48:Biomedical structure and function and related fields
|
|---|
| Research Institution | Kansai Medical University |
|---|
Principal Investigator |
|
|---|
| Project Period (FY) |
2018-06-29 – 2020-03-31
|
| Project Status |
Completed (Fiscal Year 2019)
|
| Budget Amount *help |
¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
Fiscal Year 2019: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
Fiscal Year 2018: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
|
|---|
| Keywords | 大腸がん / 転移 / 膜タンパク質 / 機能性抗体 / オルガノイド / 抗体医薬 / 創薬 / 構造解析 / X線結晶構造解析 |
|---|
| Outline of Final Research Achievements |
Colorectal cancer is driven by the accumulation of driver mutations, but the contributions of specific mutations to different steps in malignant progression are not fully understood. Different combinations of key colorectal cancer driver mutations (Apc, Kras, Tgfbr2, Trp53, Fbxw7) in intestinal epithelial cells to comprehensively investigate their roles in the development of primary tumors and metastases. RNA sequencing analysis of tumor organoids defined distinct gene expression profiles characteristic for the respective combinations of driver mutations. We found many membrane proteins upregulated in tumor organdies. We have been trying to develop the monoclonal antibody recognizing the conformational epitope against these membrane proteins and determine the structure of these membrane proteins.
|
| Academic Significance and Societal Importance of the Research Achievements |
本研究の目的は、治療薬の開発に強い社会的有用性のある「大腸がん」をモデルとした抗体医薬開発のための新しいシステムを立ち上げ、抗体医薬とターゲット分子の結合様式を原子レベルで理解するための技術基盤を構築する。一般的な創薬開発では、(1)標的分子を同定しアッセイ系を構築する、(2)リード化合物を探索し、(3)リード化合物の最適化を試みる。しかし、これら一連の過程は時間と労力がかかり成功する可能性も低い。そこで、抗体医薬の可能性のある抗体をスクリーニングし、「結晶化シャペロン」として構造解析に利用することで、新規抗体医薬の探索及びその分子メカニズムが解明され、抗体医薬の低分子化も実現可能となる。
|
