Development of a treatment for dwarfism based on the regulation of cGMP activity by optogenetic tool

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K17532
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54040:Metabolism and endocrinology-related
• Research Institution: Kyoto University
• Principal Investigator: Hirota Keisho 京都大学, 医学研究科, 助教 (20852263)
• Project Period (FY): 2020-04-01 – 2022-03-31
• Keywords: 生体イメージング / C型ナトリウム利尿ペプチド / 骨代謝 / 内分泌学

Outline of Final Research Achievements

In this study, we aim to clarify the effect of cGMP on chondrogenic differentiation in growth plate cartilage using live imaging and to apply optogenetic tools to the treatment of dwarfism. Recently, interactions between cGMP and the cAMP/PKA signaling pathway have been reported in the physiological roles of CNP. We used FRET biosensors and live imaging to show that CNP-induced PKA activation via cGMP elevation is enhanced during growth plate chondrocyte differentiation. We revealed that CNP-induced cGMP elevation activated the cAMP/PKA pathway, and clarified that this PKA activation contributed to the bone growth-promoting effect of CNP in hypertrophic chondrocytes.

Free Research Field

代謝および内分泌学関連

Academic Significance and Societal Importance of the Research Achievements

CNPは、その特異的受容体GC-Bに結合し、細胞内cGMP濃度の上昇を介して骨伸長を強力に促進する。本研究では、内軟骨性骨化におけるCNPによるPKA活性化が成長板軟骨細胞の分化に伴い増強され、肥大化軟骨細胞層の伸長を促進することが明らかとなった。今後、さらにcGMP活性制御と成長板軟骨伸長との関連を明らかにすることにより、cGMP活性の局所制御に基づく新たな低身長症の治療法の開発への基盤形成につながることが期待される。