Targeting Lysosomal Vulnerabilities in Renal Pathogenesis

项目摘要/摘要 新陈代谢应激下癌细胞的自噬功能经常被上调以循环 蛋白质和三磷酸腺苷合成的细胞成分，促进细胞存活。基于ITS 在维持细胞活力和诱导对辐射和辐射的抗性方面发挥重要作用 化疗，抑制自噬已经成为一种可行的治疗方法 已经在临床试验中进行了评估。然而，需要识别预测性生物标记物 以选择对自噬抑制剂有最佳反应的患者。我们的 初步数据显示，mTORC1调节子Redd1控制对 自噬抑制提示具有显著Redd1水平的癌症，如肾脏 细胞癌(RCC)很容易受到这种治疗方法的影响。我们的主要目标是 是研究肾癌自噬抑制敏感性的控制机制。 细胞以优化其潜在的临床应用。在目标1中，我们将确定 Redd1作为肾癌发病和自噬抑制敏感性的调节因子。在AIM 2，我们将研究PIM1抑制和上调之间的机制联系。 Redd1，重点是内质网应激。在目标3中，我们将评估影响 临床相关的自噬抑制剂联合用于肾癌治疗。

Project Summary/Abstract Autophagy is frequently upregulated in cancer cells under metabolic stress to recycle cellular components for protein and ATP synthesis to promote cell survival. Based on its important roles in maintaining cell viability and inducing resistance to radiation and chemotherapy, inhibition of autophagy has become a viable therapeutic approach that has been evaluated in clinical trials. However, there is a need to identify predictive biomarkers to enable selection of patients that may best respond to autophagy inhibitors. Our preliminary data demonstrates that the mTORC1 regulator REDD1 controls sensitivity to autophagy inhibition suggesting that cancers with significant REDD1 levels, such as renal cell carcinoma (RCC), are hypervulnerable to this therapeutic approach. Our major goal is to investigate the mechanisms that control sensitivity to autophagy inhibition in RCC cells to optimize its potential clinical application. In Aim 1, we will determine the role of REDD1 as a regulator of RCC pathogenesis and sensitivity to autophagy inhibition. In Aim 2, we will investigate the mechanistic link between PIM1 inhibition and upregulation of REDD1 with a focus on endoplasmic reticular stress. In Aim 3, we will evaluate the impact of clinically-relevant autophagy inhibitor-based combinations for RCC therapy.