Dissecting and targeting lysosomal signaling in kidney tumorigenesis

解析和靶向肾肿瘤发生中的溶酶体信号传导

• 批准号: 10594980
• 负责人: ANDREA BALLABIO
• 金额: $ 53.22万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-21 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10594980
• 关键词: Address; Autophagocytosis; Binding; Biochemical; Biogenesis; Biological Assay; Birt-Hogg-Dube Syndrome; CRISPR screen; Catabolic Process; Cell Differentiation process; Cell Separation; Cells; Cellular Metabolic Process; Cellular biology; Chromosomal translocation; Complex; Coupled; Coupling; Cultured Cells; Cystic kidney; Disease; Evaluation; Evolution; FRAP1 gene; Feedback; Folliculin; Genetic Screening; Goals; Growth; Growth Factor; Guanosine; Hereditary Disease; Histologic; Homeostasis; Hyperactivity; Kidney; Kidney Neoplasms; Knockout Mice; Link; Lysosomes; Malignant Neoplasms; Malta; Mediating; Metabolic; Metabolic Pathway; Modeling; Molecular; Mus; Names; Nature; Nuclear; Nucleotides; Nutrient; Oncogenic; Pathogenesis; Pathologic; Pathology; Pathway interactions; Phenotype; Phosphorylation; Phosphotransferases; Physiology; Play; Polycystic Kidney Diseases; Process; Proliferating; Protein Biosynthesis; Proteomics; Recycling; Regulation; Renal Cell Carcinoma; Renal Tissue; Renal carcinoma; Reporter; Research; Role; Science; Signal Pathway; Signal Transduction; Sorting; Stimulus; Structure; TFE3 gene; Testing; Therapeutic; Transcriptional Activation; Transcriptional Regulation; Transgenic Mice; Transgenic Model; Tuberous Sclerosis; Tumor Suppressor Proteins; detection of nutrient; disease phenotype; disease-causing mutation; in vivo; inhibitor; kidney cell; lipid biosynthesis; mouse model; nephrogenesis; novel; novel strategies; overexpression; pharmacologic; programs; response; transcription factor; transcriptomics; tumor growth; tumorigenesis

The lysosome, the main hub for cellular degradation and recycling processes, is emerging as a crucial signaling platform that controls cell metabolism. It is now clear that lysosomal signaling plays an important role in a variety of cancers. The Transcription Factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy, is both a substrate and a regulator of the mTORC1 lysosomal kinase complex, which drives growth and whose hyperactivation is broadly associated with cancer. Overexpression or constitutive activation of TFEB results in kidney cancer in two distinct disease entities: MiT-TFE Renal Cell Carcinoma (RCC) and Birt- Hogg-Dube' (BHD) syndrome, an inherited disease caused by mutations of folliculin (FLCN), a crucial regulator of TFEB activity. The goal of this proposal is to elucidate the mechanisms underlying TFEB-mediated kidney tumorigenesis. Emerging evidence suggest that such mechanisms may be involved in other disorders associated to kidney cancer, such Tuberous Sclerosis. Using sophisticated kidney-specific mouse transgenic models and CRE-fluorescent reporters, we will perform metabolic, biochemical, cell biology, omic and tumorigenesis assays both in vivo and in renal cultured cells with the aim of identifying the metabolic and signaling programs that underlie BHD and MiT-RCC tumorigenesis. In particular, these studies will allow us to dissect TFEB-regulated pathways that drive kidney tumorigenesis in both an mTOR- dependent and independent manner. To dissect these oncogenic programs in mechanistic depth, we will perform a detailed molecular characterization of FLCN- and mTORC1- dependent TFEB phosphorylation, coupled with candidate-based and high throughput genetic screens for novel TFEB regulators. Together, these studies will shed light on the pathogenesis of kidney tumors, and point the way toward new targets and therapeutic strategies.

溶酶体，细胞降解和再循环过程的主要枢纽，正在成为 控制细胞新陈代谢的关键信号平台。现在很明显，溶酶体 信号在多种癌症中起着重要作用。转录因子EB(TFEB)， 溶酶体生物发生和自噬的主要调节者，既是底物又是调节器 MTORC1溶酶体激酶复合体，它驱动生长，其过度激活是 广泛地与癌症有关。TFEB的过度表达或结构性激活导致 两种不同疾病的肾癌：MIT-TFE肾细胞癌(RCC)和BIRT-TFE肾细胞癌 霍格-杜贝综合征(BHD)是一种由毛囊蛋白突变(Flcn)引起的遗传性疾病， TFEB活动的关键调节者。这项提议的目的是阐明 TFEB介导的肾脏肿瘤发生的潜在机制。新出现的证据表明， 机制可能涉及其他与肾癌相关的疾病，如结节性肾癌 硬化症。使用复杂的肾脏特异的小鼠转基因模型和Cre-荧光 记者，我们将进行代谢、生化、细胞生物学、基因组和肿瘤形成分析 在体内和肾脏培养细胞中，目的是识别代谢和信号转导 BHD和MIT-RCC肿瘤发生的基础计划。特别是，这些研究将允许 美国将解剖TFEB调节的推动肾脏肿瘤发生的途径 依赖和独立的态度。从机械学角度剖析这些致癌程序 深度，我们将对Flcn-和mTORC1-进行详细的分子表征。 依赖的TFEB磷酸化，结合基于候选和高通量的基因 用于新型TFEB调节器的屏幕。综上所述，这些研究将有助于阐明该病的发病机制。 肾脏肿瘤的治疗，并为新的靶点和治疗策略指明了方向。