| Budget Amount *help |
¥2,431,000 (Direct Cost: ¥1,870,000、Indirect Cost: ¥561,000)
Fiscal Year 2011: ¥1,378,000 (Direct Cost: ¥1,060,000、Indirect Cost: ¥318,000)
Fiscal Year 2010: ¥1,053,000 (Direct Cost: ¥810,000、Indirect Cost: ¥243,000)
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| Research Abstract |
Glucagon-like peptide-1(GLP-1) elevates intracellular concentration of cAMP([cAMP]) and facilitates glucose-dependent insulin secretion in pancreaticβ-cells. However, because of complex interactions between signaling factors and effectors, the detailed mechanism underlying elevated insulin secretion has not been elucidated. We thus utilized 'bioinformatics' to quantitatively analyze the GLP-1 effects. First, we reconstructed a minimal mathematical model of GLP-1 receptor signal transduction, which involves GLP-1 receptor, Gs protein, adenylate cyclase(AC), phosphodiesterase(PDE). By fitting this theoretical reaction scheme to key experimental records of the GLP-1 response, the parameters determining individual reaction steps were estimated. The model reconstructed satisfactorily the dynamic changes in cAMP, and predicted the activities of cAMP effectors, protein kinase A(PKA) and cAMP-regulated guanine nucleotide exchange factor(cAMP-GEF or Epac) during GLP-1 stimulation. The simulations also predicted the presence of two sequential desensitization steps of the GLP1 receptor that occur with fast and very slow reaction rates. The cross talk between glucose-and GLP-1-dependent signal cascades for cAMP synthesis was well reconstructed by integrating the direct regulation of AC and PDE by [Ca^<2+>]. We finally incorporated the GLP-1 signaling cascade model into the β-cell model. By cording the PKA and Epac induced modulation on ion channels(L-type Ca^<2+> currents, Voltage-dependent K+channels, ATP-dependent K+channels), the GLP-1 effects on the magnitude as well as the amplitude of bursts of action potentials were well reconstructed. We will be able to quantitatively analyze the effects of GLP-1 on each signaling effectors on membrane excitability and Ca^<2+> signaling when models of Ca^<2+> releasing channels on endoplasmic reticulum(ER) are completed.
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