Functional analysis of Erythropoietin that is produced in epithelial cells independently of hypoxic stimuli

• Project/Area Number: 18K19416
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 48:Biomedical structure and function and related fields
• Research Institution: Tohoku University
• Principal Investigator: Shimizu Ritsuko 東北大学, 医学系研究科, 教授 (40226262)
• Project Period (FY): 2018-06-29 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000); Fiscal Year 2019: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2018: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: エリスロポエチン / 腎性貧血 / 創薬 / GATA転写因子

Outline of Final Research Achievements

We focused on a GATA-binding motif within the Epo gene promoter-proximal region, which is involved in constitutive suppression of Epo gene expression in epithelial cells in mice. We have established two lines of mice carrying an allele that was deleted for the GATA-binding motif by means of Crispr/Cas9 system. The heterozygous mice could be born alive with the expected Mendelian frequency and seemed to grow up normally. We have expected that Epo gene expression is constitutively activated in the heterozygous mice, however, the mice showed no remarkable changes in the hematopoietic indices. In addition, the expression of Epo gene in the lung epithelial cells was not activated in the heterozygous mice. We are planning to examine the hematopoietic indices and Epo gene expression in the epithelial cells of mice carrying homozygous deletion of the GATA-binding motif.

Academic Significance and Societal Importance of the Research Achievements

近年、低酸素誘導因子（HIF）の安定化を目的としたプロリン水酸化酵素阻害剤が開発され、検証的臨床試験の結果からある程度の貧血改善が得られることが明らかにされた。しかし、既に低酸素に晒されているにもかかわらずEPO産生能が低下している腎性貧血患者のEPO産生細胞に、さらに疑似低酸素状態（HIFの安定化）を増強させることで、どの程度の治療効果が得られるかが疑問視されている。また、全身性のHIF安定化による危険性を懸念する研究者も多い。以上のことから、腎性貧血患者において障害を受けていない上皮系細胞に焦点を当てた本研究は臨床的応用可能な治療薬創出につながると考えられる。

Research Products

• [Presentation] 転写因子GATA2によるサイトカイン産生亢進を介した腎臓での炎症促進メカニズム (2019)
  • Author(s): 森口尚、于磊、金子寛、山本雅之、清水律子
  • Organizer: 第91回生化学会大会
• [Book] 未来型血液治療学 (2019)
  • Author(s): 清水律子（分担執筆）
  • Total Pages: 285
  • Publisher: 中外医学社
  • ISBN: 9784498225183