Compartmentation of cAMP and Its Coupling to Epac

描述（由申请人提供）：我们研究的目的是阐明在控制信号传导特异性中建立cAMP区室化的机制，以及确定cAMP微结构域的功能重要性。cAMP通过与下游效应物如cAMP依赖性蛋白激酶（PKA）和由cAMP直接激活的交换蛋白（Epac）偶联来介导许多细胞过程。由于cAMP在不同的亚细胞位点产生并在整个细胞中快速扩散，因此必须调节信号传播以实现所需的细胞反应。然而，直到最近才有工具可以有效地探索这些控制机制。受损的cAMP信号传导具有临床意义，例如肥胖和II型糖尿病。因此，更好地了解cAMP信号可能会导致这些临床疾病的新治疗方法。我们研究的具体目的是进一步开发和表征基于FRET的cAMP指标，以阐明β-肾上腺素能受体信号传导的时空动力学，并使用这些指标和体外测定来确定线粒体cAMP的下游效应子和功能意义。

DESCRIPTION (provided by applicant): The goal of our research is to elucidate the mechanisms that establish cAMP compartmentation in controlling signaling specificity as well as determine the functional importance of cAMP microdomains. cAMP mediates many cellular processes by coupling to downstream effectors such as cAMP dependent protein kinase (PKA) and exchange protein directly activated by cAMP (Epac). Because cAMP is produced at distinct subcellular sites and diffuses rapidly throughout the cell, mechanisms must regulate signal propagation in order to achieve a desired cellular response. However, only recently have tools become available to effectively explore these mechanisms of control. Impaired cAMP signaling has clinical implications such as obesity and type II diabetes. Therefore, a better understanding of cAMP signaling may lead to new therapeutic approaches for these clinical conditions. The specific aims of our research are to further develop and characterize FRET-based cAMP indicators to elucidate the spatiotemporal dynamics of beta-adrenergic receptor signaling and use these indicators and in vitro assays to determine the downstream effectors and functional significance of mitochondrial cAMP.