| Project/Area Number |
16K09820
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Multi-year Fund |
|---|
| Section | 一般 |
|---|
| Research Field |
Hematology
|
|---|
| Research Institution | Yamagata University |
|---|
Principal Investigator |
|
|---|
| Research Collaborator |
SOURI Masayoshi
OSAKI Tsukasa
YOKOYAMA Chikako
|
|---|
| Project Period (FY) |
2016-04-01 – 2019-03-31
|
| Project Status |
Completed (Fiscal Year 2018)
|
| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
|
|---|
| Keywords | 血栓止血 / 自己免疫疾患 / 致死性出血病 / 抗第XIII/13因子抗体 / 厚労省指定難病 |
|---|
| Outline of Final Research Achievements |
By using plasma and serum of a number of Japanese patients with autoimmune Factor XIII/13 (F13) deficiency (AiF13D), their anti-F13A and anti-F13B antibodies were analyzed in detail. Epitopes of patients’ antibodies were also roughly mapped. However, antibodies of each patient must be oligoclonal or polyclonal so that their exact functions and epitopes cannot be determined.
Therefore, anti-human F13A monoclonal antibodies’ clones were produced from a single case for the first time, and their biding pattern, inhibitory mechanisms as well as ectopic sites were identified. Rat anti-F13B monoclonal antibodies were generated and used for the structure-function relationship analyses of F13B.
When whole exome analyses were carried out in 20 AiF13D cases, large numbers of nucleotide sequences which differ from the Japanese reference sequences were identified; These are included in the genes coding HLA-A, -B, -F and -DQA1, etc., which are closely related to the antigen-presenting function.
|
| Academic Significance and Societal Importance of the Research Achievements |
世界で初めてヒト抗F13Aモノクローン抗体産生クローンを作製することに成功したので、それぞれの抗体がF13Aの何処に結合するのか、何故F13AとF13Bの異種４量体形成、F13活性化、活性型F13の触媒能を阻害するのかなどを明らかにした。これらは、抗F13A自己抗体検出法の陽性対照に利用することができるのみならず、将来F13機能を阻害する抗体医薬に応用できる可能性がある。
20名のAiF13D症例のDNAを全エクソーム解析して、日本人の標準塩基配列と異なる多数の部位を同定した。それらの一部は抗原提示機能に深く関与するので、自己抗体を産生し易く本疾患に罹患する傾向を生じているかも知れない。
|
