Control of vesicular trafficking in the hepatocyte

摘要 这是艾伦·沃尔科夫博士和他的团队第一次竞争性地更新合作项目 Ana Maria Cuervo博士研究内吞/溶酶体过程在肝脏病理生理学中的作用。在.期间 在前一阶段，我们开发了技术来剖析调节人口贩运的分子机制 参与这些过程的囊泡成分。我们还做出了最初的发现，内吞 自噬途径在功能上是紧密相关的，这些过程的功能障碍可能导致 导致肝脏脂肪和碳水化合物代谢失调。我们现在打算继续这方面的研究。 专注于一种选择性的自噬形式，伴侣介导的自噬(CMA)来测试我们的工作 假设CMA功能障碍可能导致代谢综合征的发病，非 酒精性脂肪肝(NAFLD)和肝纤维化。 我们认为，1)由于饮食挑战和衰老导致的肝脏CMA活性降低有助于 加速脂肪肝疾病的进展和2)增强这种形式的自噬可能是一种 成功的干预措施预防脂肪肝的进展 为了验证这一假设，我们打算：1)确定饮食诱导的肝脏CMA的分子基础 小鼠模型和NAFLD患者的功能障碍；2)CMA的时空序列特征 脂肪肝和肝纤维化过程中的变化；3)检测CMA是否有遗传或化学增强 有效地保护脂质挑战肝脏免受脂肪毒性和疾病进展的影响。 意义：这项研究将阐明CMA功能衰退是如何导致脂肪肝和 肝纤维化。我们的发现可能有助于开发新的方法来保护肝脏免受脂肪毒性的影响 减少进展为肝纤维化。

Abstract This is the first competing renewal of a collaborative project between the groups of Dr. Allan Wolkoff and Dr. Ana Maria Cuervo to investigate the role of endocytic/lysosomal processes in liver pathophysiology. During the previous period, we developed technology to dissect the molecular mechanism regulating trafficking of the vesicular components that participate in these processes. We also made the original discovery that endocytic and autophagic pathways are tightly interrelated functionally and that dysfunction of these processes can lead to dysregulation of lipid and carbohydrate metabolism in the liver. We now intend to continue this line of studies focusing on a selective form of autophagy, chaperone-mediated autophagy (CMA) to test our working hypothesis that CMA malfunctioning could contribute to the pathogenesis of metabolic syndrome, non- alcoholic fatty liver disease (NAFLD) and liver fibrosis. We propose that 1) reduced hepatic CMA activity as a result of dietary challenges and aging contributes to accelerate progression of fatty liver disease and that 2) enhancing this form of autophagy could be a successful intervention to prevent progression of fatty liver Disease To test this hypothesis we intend to: 1) determine the molecular basis of dietary-induced hepatic CMA dysfunction both in mouse models and NAFLD patients; 2) characterize the spatiotemporal sequence of CMA changes in the fatty liver and during liver fibrosis; 3) test if genetic or chemical enhancement of CMA is effective in protecting lipid challenged livers against lipotoxicity and disease progression. Significance: This study will elucidate how a functional decline of CMA contributes to fatty liver disease and liver fibrosis. Our findings could help in developing new approaches to protect the liver from lipotoxicity and to reduce progression to liver fibrosis.