Mechanisms of lipid droplet trafficking in hepatocellular carcinoma

肝细胞癌中脂滴运输的机制

基本信息

批准号：
10644812
负责人：
Micah Schott
金额：
$ 21.53万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-02 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10644812
关键词：
Acceleration Acid Lipase Address Advisory Committees Affect Alcohol consumption Applications Grants Autophagocytosis Binding Biochemistry Biological Cancer Biology Cancer Center Cancer Etiology Cancer Model Catabolism Cell Energetics Cell Fractionation Cell Proliferation Cells Cellular biology Cessation of life Cirrhosis Data Development Disease Docking Endosomes Energy Supply Environment Enzymes Exhibits Fatty Liver Future Goals Growth Guanosine Triphosphate Phosphohydrolases HepG2 Hepatocyte Homeostasis Human Incidence Injections Investigation Knowledge Laboratories Lipids Liver Liver diseases Lysosomes Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of liver Measures Mediating Medical center Metabolic Microscopy Molecular Monomeric GTP-Binding Proteins Mus Nebraska Obesity Oncogenes Outcome Pathway interactions Patients Phenotype Physiology Play Primary carcinoma of the liver cells Process Research Research Project Grants Risk Factors Role Signal Transduction Sleeping Beauty Steatohepatitis Surface Tail Testing Therapeutic Transposase Universities Veins Vesicle Work anticancer research cancer cell clinically relevant fatty liver disease hepatocellular carcinoma cell line in vivo in vivo Model lipid metabolism liver cancer model mouse model novel public health relevance recruit superresolution microscopy therapeutic target trafficking tumor tumor growth tumorigenesis

项目摘要

Project Summary/Abstract Hepatocellular carcinoma (HCC) is the most common form of liver cancer and fourth leading cause of cancer deaths worldwide. The incidence of HCC is rising as key risk factors including obesity and heavy alcohol consumption are accelerating at rates greater than ever before. These risk factors drive hepatic steatosis and steatohepatitis, marked by the extreme accumulation of lipid droplets (LDs) in hepatocytes, leading to cirrhosis and HCC. While lipid synthesis a well-described phenotype in HCC, the role of LDs in propagating tumor formation and growth is poorly understood. Preliminary data from our laboratory suggests that the small GTPase Rab5 localizes to LDs and plays a critical role in trafficking to the lysosome, where LDs are catabolized by lysosomal acid lipase (LAL). Moreover, both Rab5 and LAL expression are increased in HCC tumors, consistent with cell biological studies showing elevated lipophagy in HCC cell lines vs normal hepatocytes. These data support the hypothesis that Rab5-LD interaction drives HCC tumor growth via lysosomal catabolism. In Aim 1, we will determine the mechanisms of Rab5 binding to LDs in HCC, and how this interaction impacts cancer cell energetics and proliferation. In Aim 2, we will determine the impact of Rab5-mediated lipophagy on HCC tumor growth in vivo using a sleeping beauty transposon transposase (SBTT) mouse model in which oncogenes are delivered to hepatocytes via hydrodynamic tail vein injection (HTVI). The results gained from the proposed research will provide a mechanistic understanding of lipid droplet trafficking and catabolism in hepatocellular carcinoma progression. Moreover, this research will aid in future development of larger research project grant applications.

项目概要/摘要肝细胞癌 (HCC) 是最常见的肝癌形式，位居第四全球癌症死亡的主要原因。 HCC 的发病率正在上升，成为主要危险因素包括肥胖和酗酒的速度比以往任何时候都快前。这些危险因素会导致肝脂肪变性和脂肪性肝炎，其特点是极端肝细胞中脂滴（LD）的积累，导致肝硬化和肝癌。尽管脂质合成 HCC 中一种已被充分描述的表型，LD 在肿瘤增殖中的作用人们对它的形成和生长知之甚少。我们实验室的初步数据表明小 GTP 酶 Rab5 定位于 LD，并在贩运到溶酶体，LD 被溶酶体酸性脂肪酶 (LAL) 分解代谢。此外，Rab5 和 LAL 表达在 HCC 肿瘤中增加，与细胞生物学研究一致显示与正常肝细胞相比，HCC 细胞系的自噬能力升高。这些数据支持 Rab5-LD 相互作用通过溶酶体分解代谢驱动 HCC 肿瘤生长的假设。在目标 1 中，我们将确定 Rab5 与 HCC 中 LD 结合的机制，以及如何结合相互作用影响癌细胞能量和增殖。在目标 2 中，我们将确定使用睡美人研究 Rab5 介导的脂肪吞噬对体内 HCC 肿瘤生长的影响转座子转座酶 (SBTT) 小鼠模型，其中癌基因被传递至肝细胞通过尾静脉水动力注射（HTVI）。从拟议的研究中获得的结果将提供对脂滴运输和分解代谢的机制理解肝细胞癌进展。此外，这项研究将有助于未来的发展较大的研究项目资助申请。