Patched-dependent regulation of intracellular endocannabinoid trafficking and its function in signalling and metabolism (19)

Hedgehog信号通路在调节组织生长、分化和动态平衡方面具有保守的功能。这条途径的转录和代谢输出似乎都是单独控制的，但区分它们的机制尚不清楚。我们已经证明，内源性大麻素通过与7通路TM蛋白平滑(Smo)结合并破坏其稳定性，从而抑制HH途径的转录输出。HH受体补丁通过控制这些脂质信号分子在细胞内的运输来调节Smo的活性。除了对Smo的影响外，Patted还调节内源性纳比诺到线粒体的运输。这一建议旨在1)揭示内源性大麻素进入SMO的细胞内运输途径；2)确定促进内源性大麻素动员到线粒体的分子机制；3)确定线粒体中内源性大麻素的存在如何影响其活性。

The Hedgehog signaling pathway has conserved functions in regulating tissue growth, differentiation and homeostasis. The pathway has both transcriptional and metabolic outputs that appear to be separately controlled, but the mechanisms that distinguish them are unclear. We’ve shown that endocannabinoids repress the transcriptional output of the Hh pathway by binding to and destabilizing the 7 pass TM protein Smoothened (Smo). The Hh receptor Patched regulates Smo activity by controlling the intracellular trafficking of these lipid signaling molecules. Independent of its effects on Smo, Patched also modulates trafficking of endocnanabinoids to mitochondria. This proposal aims to 1) uncover the intracellular trafficking pathways through which endocannabinoids access Smo 2) identify the molecular machinery that promotes endocannabinoid mobilization to mitochondria and 3) determine how the presence of endocannabinoids in mitochondria influence their activity.