Potential novel angiogenic therapy through BubR1 gene transfer for Critical Limb Ischemia

2019 Fiscal Year Final Research Report

• Project/Area Number: 16K10662
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular surgery
• Research Institution: International University of Health and Welfare
• Principal Investigator: Matsumoto Takuya 国際医療福祉大学, 医学部, 主任教授 (20374168)
• Co-Investigator(Kenkyū-buntansha): 古山 正 九州大学, 大学病院, 講師 (00419590) ; 前原 喜彦 福岡歯科大学, 口腔歯学部, 客員教授 (80165662)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Keywords: 重症虚血肢 / 血管新生因子 / BubR1 / 老化 / 細胞周期遺伝子

Outline of Final Research Achievements

We generated a BubR1L/- mouse strain with reduced BubR1 expression as low as 15% of the normal level without any abnormalities in appearance including progressive aneuploidy, cataracts, lordokyphosis, loss of subcutaneous fat, impaired wound healing, shortened lifespan, and infertility. Therefore, these mice may represent a good in vivo critical limb ischemic model for studying angiogenesis. Using BubR1L/- mice, we showed that BubR1 insufficiency led to limb- loss in the critical limb ischemia model, characterized by an increase in tissue granulation and inflammatory cell invasion. Additionally, we showed that VEGF expression decreased in ischemic calf muscle. BubR1 insufficiency suppresses the increase in HIF1α after experimental critical limb ischemia.
BubR1　insufficiency impairs angiogenesis and results in limb-loss in ischemic hind limbs. BubR1 may be a crucial angiogenic factorand might be beneficial for the treatment of limb ischemia.

Free Research Field

Vascular biology

Academic Significance and Societal Importance of the Research Achievements

重症虚血肢に於けるBubR1の分子機構解析は皆無である。また、老化に伴うBubR1の発現低下による血管新生への影響の解明も必要である。今回の研究で我々が新たに解明した知見は、老化の血管新生メカニズムへの解明に大きく寄与するばかりか、臨床応用に直接結びつく重要な研究課題である。今後は、BubR1を補充することにより高齢化社会における重症虚血肢に対する血管新生療法の新たな治療選択の一つとなる可能性が示唆された。