研究成果の概要（和文）：喘息の病態を気道平滑筋の表現型の変化として捉え、鍵となる蛋白を検索し、根元的な分子標的治療の確立を目的とした。その結果、病態の大部分は収縮性、増殖性の表現型の変化で生じ、それらの機序として、Ca2+-activated K+ channel/voltage-dependent Ca2+ channel の連関に由来する Ca2+ dynamics、および、RhoA/Rho-kinase 系を介する Ca2+ sensitization の関与を解明した。これらの Ca2+ signaling は、喘息治療のあらたな標的蛋白と考えられる。
研究成果の概要（英文）：Alteration of contractility in airway smooth muscle (ASM) contributes to airflow limitation, airway hyperresponsiveness (AHR), and beta2-adrenergic desensitization. Alteration of synthesis contributes to airway remodeling via facilitation of the proliferation and migration in ASM. In our observation, Ca2+ dynamics through the large-conductance Ca2+-activated K+ channel/L-type voltage-dependent Ca2+ channel linkage, and Ca2+ sensitization through the RhoA/Rho-kinase pathway contribute not only to alterations in the contractile phenotype involved in airflow limitation, AHR and tolerance to beta2-adrenergic receptors, but also to alteration of the synthetic phenotype involved in airway remodeling. The Ca2+ signaling also contribute to the synergism (cross talk) in combination of beta2-adrenergic receptor agonists with muscarinic receptor antagonists. Therefore, the phenotype change in ASM via the Ca2+ signaling may be a novel target for development of asthmatic agents.
気道平滑筋の遊走能と収縮能の制御に基づく喘息分子標的療法
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