2018 Fiscal Year Final Research Report
HSP70 targeting therapy for retinitis pigmentosa
| Project/Area Number |
16K11335
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Multi-year Fund |
|---|
| Section | 一般 |
|---|
| Research Field |
Ophthalmology
|
|---|
| Research Institution | Suzuka University of Medical Science |
|---|
Principal Investigator |
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
古川 絢子 鈴鹿医療科学大学, 薬学部, 助教 (10455537)
杉谷 加代 金沢大学, 保健学系, 助教 (20162258)
|
|---|
| Research Collaborator |
OKUMURA Takaaki
|
|---|
| Project Period (FY) |
2016-04-01 – 2019-03-31
|
| Keywords | 網膜色素変性症 / HSP70 / カルボニル化 / カルシウム / カルパイン |
|---|
| Outline of Final Research Achievements |
Retinal degenerative diseases, such as retinitis pigmentosa, are characterized by night blindness and peripheral vision loss caused by the slowly progressive loss of photoreceptor cells. A comprehensive molecular mechanism of the photoreceptor cell death remains unclear. We reported that heat shock protein 70 (HSP70), which has a protective effect on neuronal cells, was cleaved by a calcium-dependent protease, calpain, in N-methyl-N-nitrosourea (MNU)-treated mice retina. Carbonylated HSP70 is much more vulnerable than noncarbonylated HSP70 to calpain cleavage. However, it was not known whether protein carbonylation occurs in MNU-treated mice retina. In this study, we clearly show protein carbonylation-dependent photoreceptor cell death induced by MNU in mice. Therefore, protein carbonylation and subsequent calpain-dependent cleavage of HSP70 are key events in MNU-mediated photoreceptor cell death. Our data provide a comprehensive molecular mechanism of the photoreceptor cell death.
|
| Free Research Field |
網膜変性
|
| Academic Significance and Societal Importance of the Research Achievements |
網膜色素変性症(RP)の最終病態は視細胞死の変性脱落であるため、その新たな病態メカニズム解明が新規治療戦略につながる。我々の仮説では分子シャペロンであるHSP70 が、カルボニル化・分解を受けることでミスフォールディングが増え、広範囲のプロテオスタシス破綻が起き、次いでリソソーム酵素であるカテプシンが漏出することで二次的プロテオスタシス破綻といった悪循環をもたらす、独創的で新たなRP 病態メカニズムを想定している。本研究で新たに提唱するカルボニル化阻害剤、HSP70 誘導剤、カテプシン阻害剤がRP に有効であれば新たな治療戦略のひとつとなり、多くのRP 患者に光を戻すことができると信じている。
|
