权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Targeting Lysosomal Vulnerabilities in Renal Pathogenesis

针对肾脏发病机制中的溶酶体脆弱性

基本信息

批准号：
10570295
负责人：
Jennifer S Carew
金额：
$ 47.12万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-10 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10570295
关键词：
ATP Synthesis Pathway Address Apoptosis Apoptotic Autophagocytosis CRISPR/Cas technology Cell Survival Chemotherapy and/or radiation Clear Cell Clear cell renal cell carcinoma Clinical Clinical Trials Clinical Trials Design Competence Data Dependence Dose Drug resistance Exhibits FRAP1 gene Failure Genetic Goals Homeostasis Hydroxychloroquine Hypersensitivity Hypoxia Immune checkpoint inhibitor Kidney Link Lysosomes Malignant - descriptor Malignant Epithelial Cell Malignant Neoplasms Mediating Mediator Medical Metabolic stress Modeling Organelles PIM1 gene Pathogenesis Pathway interactions Patient Selection Patient-Focused Outcomes Phosphotransferases Play Protein Biosynthesis Proteins Recycling Regimen Renal Cell Carcinoma Reporting Resistance Role Starvation Stress Testing Therapeutic Tumor Suppressor Proteins Up-Regulation cancer cell cancer type chemotherapy clinical application clinical translation clinically actionable clinically relevant endoplasm endoplasmic reticulum stress improved outcome inhibition of autophagy inhibitor kinase inhibitor mouse model novel novel strategies overexpression patient derived xenograft model pharmacologic predictive marker proto-oncogene protein pim rational design response standard of care transcription factor transcriptome tumor tumor progression

项目摘要

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.

项目总结/摘要在代谢应激下，癌细胞的自噬经常上调以进行回收蛋白质和ATP合成的细胞组分，以促进细胞存活。基于其在维持细胞活力和诱导对辐射的抗性方面的重要作用，化疗，抑制自噬已经成为一种可行的治疗方法，在临床试验中进行了评估。然而，需要识别预测性生物标志物以选择对自噬抑制剂反应最好的患者。我们初步数据表明，mTORC 1调节因子REDD 1控制对自噬抑制表明，具有显著REDD 1水平的癌症，如肾癌，细胞癌（RCC）对这种治疗方法非常脆弱。我们的主要目标目的是研究肾细胞癌中控制自噬抑制敏感性的机制细胞，以优化其潜在的临床应用。在目标1中，我们将确定 REDD 1作为RCC发病机制和对自噬抑制敏感性的调节剂。在Aim中 2，我们将研究PIM 1抑制和上调之间的机制联系， REDD 1，重点是内质网应激。在目标3中，我们将评估用于RCC治疗的临床相关的基于自噬通道的组合。