| Project/Area Number |
22K16264
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 53050:Dermatology-related
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| Research Institution | Yamaguchi University |
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Principal Investigator |
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| Project Period (FY) |
2022-04-01 – 2024-03-31
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| Project Status |
Completed (Fiscal Year 2023)
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| Budget Amount *help |
¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
Fiscal Year 2023: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2022: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
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| Keywords | 遺伝性血管性浮腫 / HAE / SERPING1 / siRNA / 遺伝性血管性浮腫I型 / HAE1 / C1INH / 遺伝性血管性浮腫Ｉ型 |
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| Outline of Research at the Start |
遺伝性血管性浮腫I型（HAE1）の患者に同定されたSERPING1遺伝子変異c.449C>T由来の変異型蛋白（p.S150F）が野生型蛋白に対して
dominant-negative effectを発揮するという特徴を踏まえ、変異型アレルからの発現をmRNAレベルで阻害することで発症を抑制するような治療が理論上は可能である。本研究では、c.449C>TアレルからのSERPING1遺伝子の発現を最も特異的かつ効率よく低下させるsiRNAを作製し、蛋白レベルでその効果を検証する。
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| Outline of Final Research Achievements |
In this study, we aimed to identify siRNA which specifically suppressed expression of the mutant C1INH and restored the secretion of the wild-type C1INH in a missense SERPING1 gene mutation c.449C>T (p.S150F) which was previously identified in patients with HAE type I. First, we designed siRNAs targeting the mutant SERPING1-mRNA, and identified a siRNA significantly reducing the expression of the mutant C1INH without affecting the expression of the wild-type C1INH. Second, we demonstrated that the expression of the wild-type C1INH was significantly restored in both the lysate and the medium by the siRNA on the condition that the wild-type and the mutant C1INH were co-overexpressed. This study shows that the dominant-negative effect against the wild-type C1INH is suppressed by the knockdown of the expression of the mutant C1INH using siRNA.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究では、1種類のSERPING1遺伝子変異について、変異型C1INHの発現をsiRNAで特異的にノックダウンさせることによってdominant-negative効果を抑制して野生型C1INHの分泌量の回復に成功した。本研究によりsiRNAを用いたHAEⅠ型の新たな治療薬開発の可能性が示唆された。
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