| Project/Area Number |
21K09409
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Multi-year Fund |
|---|
| Section | 一般 |
|---|
| Review Section |
Basic Section 56030:Urology-related
|
|---|
| Research Institution | Juntendo University (2023)
Dokkyo Medical University (2021-2022) |
|---|
Principal Investigator |
Ide Hisamitsu 順天堂大学, 医学部, 特任教授 (00301383)
|
|---|
| Project Period (FY) |
2021-04-01 – 2024-03-31
|
| Project Status |
Completed (Fiscal Year 2023)
|
| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2023: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
|
|---|
| Keywords | 前立腺癌 |
|---|
| Outline of Research at the Start |
加齢と伴に体内に蓄積した老化細胞はさまざまな炎症性蛋白質を高発現し周囲に分泌する細胞老化随伴分泌現象：SASP (Senescence-associated secretory phenotype)を引き起こす。老化細胞ではDNAメチル化酵素やヒストンメチル化酵素の発現低下によってエピジェネティックな遺伝子発現抑制機構が破綻し、様々なSASP遺伝子の発現が誘導される。本研究では、新規前立腺癌発症モデルであるDNA脱メチル化酵素UTXを前立腺特異的にノックアウトしたマウスを用いて、脂肪負荷と老化によるSASPが前立腺癌細胞の悪性化や去勢抵抗性獲得に関与しているのかを検証する。
|
| Outline of Final Research Achievements |
Using a novel prostate cancer onset model in which the DNA demethylation enzyme UTX was specifically knocked out in the prostate, we investigated whether SASP (senescence-associated secretory phenotype) induced by fat loading and aging contributes to the malignancy and acquisition of castration resistance in prostate cancer cells. As a model, we created prostate-specific Utx-deficient mice. In male mice with prostate-specific Utx deletion, prostate cancer development was observed due to the stress from a high-fat diet. Prostate cancer occurred after 8-9 weeks, with a malignancy graded at Gleason grade 3-4. Using senescence-associated β-galactosidase (SA β-Gal) as an aging marker and evaluating through immunohistochemical staining, an increase in β-Gal positive cells was observed with cancer development. These research results suggest a mechanism of cancer progression mediated by SASP in Utx-deficient mice.
|
| Academic Significance and Societal Importance of the Research Achievements |
モデルとして、前立腺特異的なUtx欠失マウスを作製し、前立腺でUtxを欠失したオスマウスでは、脂肪食によるストレスから前立腺癌の発癌がみられた。ヒストン・クロマチン修飾因子を標的とした前立腺癌モデルマウスはまったく新しい疾患モデルになると考えられ、SASPの解析とともに得られた結果は前立腺癌発症の分子機構に新たな知見をもたらし、新規治療法開発に役立つ可能性が期待される。
|
