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、分化和稳态中具有保守的功能。该途径具有转录和代谢输出，它们似乎是单独控制的，但区分它们的机制尚不清楚。我们已经表明，内源性大麻素抑制Hh途径的转录输出结合和不稳定的7通TM蛋白Smoothened（Smo）。Hh受体Patched通过控制这些脂质信号分子的细胞内运输来调节Smo活性。独立于其对Smo的影响，Patched还调节endocnanabinoids向线粒体的运输。该提案旨在：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向线粒体动员的分子机制; 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.