2021 Fiscal Year Final Research Report
Development of innovative dementia antibody therapy targeting microglial membrane proteins with few side effects
| Project/Area Number |
20K21577
|
|---|
| Research Category |
Grant-in-Aid for Challenging Research (Exploratory)
|
| Allocation Type | Multi-year Fund |
|---|
| Review Section |
Medium-sized Section 52:General internal medicine and related fields
|
|---|
| Research Institution | Tottori University |
|---|
Principal Investigator |
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
岩田 正明 鳥取大学, 医学部, 教授 (40346367)
|
|---|
| Project Period (FY) |
2020-07-30 – 2022-03-31
|
| Keywords | ミクログリア / xCT / xc-系 / グルタミン酸 / ファージディスプレイ / アルツハイマー病 / 認知症 |
|---|
| Outline of Final Research Achievements |
In order to establish antibody therapy for dementia, we generated antibodies targeting xCT. Since xCT is a protein whose expression is induced in the microglial cell membrane, and release glutamate to the extracellular space, "system xc-/xCT" is a promising target for antibody therapy. Five candidate antibodies were obtained by the phage display method using the amino acid sequence of the extracellular domain. Western blotting confirmed that all the obtained antibodies reacted to xCT. In addition, we confirmed the induction of xCT expression in microglial cell lines by adding polymerized Aβ as a stimulus related to Alzheimer's disease. Currently, we are conducting tissue immunostaining using AD mouse model sections and xCT inhibition experiments using antibodies using cells.
|
| Free Research Field |
病態生化学，神経科学，神経内科学，生化学
|
| Academic Significance and Societal Importance of the Research Achievements |
近年，抗体を利用した認知症治療の研究が進められてきた．アルツハイマー病におけるAβ抗体療法もその一つだが，有意な効果が認められないか，自己免疫性脳炎等の副作用により，実用レベルには至っていない．抗体治療を試みる場合，「いかに正常タンパク質を攻撃しないようにするか」が重要であり，標的とすべき抗原は，正常時には発現がなく，認知症時にのみ発現誘導されるものが理想である．本研究では条件を満たす抗原として，シスチン・グルタミン酸交換系トランスポーター「System xc- (xc-系)」の構成分子 xCT に注目し，認知症全般に応用可能な，かつ副作用の少ない抗体療法の可能性を探る．
|
