TraPPs - Tracking of Phosphoinositide Pools - Key Signalling Components in Cell Migration and Polarisation

膜动力学调节细胞极性、囊泡运输、迁移、生长、增殖、分化等。在所有膜脂质中，磷酸肌醇在这些过程中起中心作用（Wymann & Marone 2005 Curr Opin Cell Biol; Lindmo & Stenmark 2006 J Cell Sci; Simonsen & Stenmark 2007 Nat Chem Biol）。尽管在生理学和疾病中突出了突出的3-磷酸化磷酸肌醇如PtdIns（3，4，5）P3和PtdIns（3）P的作用（Wymann等人，2003 TiPS），但这些脂质的动力学和定位仍然知之甚少。陷阱将提供磷酸肌醇通量和所需脂质修饰酶（例如PI 3 K、脂肪酶和脂质磷酸酶）的动态和精细视图。脂质修饰酶将动态靶向不同的细胞位置，脂质相互作用蛋白质应被操纵以显示其游离或脂质结合状态。最后，磷脂修饰酶的活性状态将通过活细胞中酶-底物复合物的形成来成像（Yudushkin等人，2007，Science）。脂质修饰酶的激活将与局部上游信号传导和特异性细胞应答相关。细胞，遗传苍蝇和小鼠模型将用于验证未发现的分子机制。这项工作为脂质信号传导的更广泛的系统生物学方法提供了基础，并将阐明与癌症和炎症相关的动态细胞过程。

Membrane dynamics modulate cell polarity, vesicular trafficking, migration, growth, proliferation, differentiation, and more. Of all membrane lipids, phosphoinositides play a central role in these processes (Wymann & Marone 2005 Curr Opin Cell Biol; Lindmo & Stenmark 2006 J Cell Sci; Simonsen & Stenmark 2007 Nat Chem Biol). Although a role for the prominent 3-phosphorylated phosphoinositides such as PtdIns(3,4,5)P3 and PtdIns(3)P has been highlighted in physiology and disease (Wymann et al. 2003 TiPS), dynamics and localization of these lipids are still poorly understood. TraPPs will provide a dynamic and refined view of phosphoinositide flux, and required lipid modifying enzymes, e.g. PI3Ks, lipases, and lipid phosphatases. Lipid-modifying enzymes will be targeted dynamically to distinct cellular locations, and lipid-interacting proteins shall be manipulated to display their free or lipid-bound state. Finally, the activity state of phospholipid-modifying enzymes will be imaged by the formation of enzyme-substrate complexes in living cells (Yudushkin et al., 2007, Science). Activation of lipid modifying enzymes will be linked to localized upstream signalling and specific cell responses. Cellular, genetic fly and mouse models will be used to validate the uncovered molecular mechanisms. This work provides the basis for a broader systems biology approach of lipid signaling, and will elucidate dynamic cellular processes relevant to cancer and inflammation.