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

Sphingosine kinase 2 in sexual dimorphism of hepatocellular carcinoma

鞘氨醇激酶2在肝细胞癌性别二态性中的作用

基本信息

批准号：
10521724
负责人：
Christopher D Green
金额：
$ 39.02万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
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：
2022-09-01 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10521724
关键词：
Androgen Metabolism Androgen Receptor Androgens Animal Model Binding Cancer Etiology Carcinogens Cell Cycle Cell Nucleus Cells Ceramides Cessation of life Cholesterol Homeostasis Clinical Trials Data Development Diet Disease Enzymes Equilibrium Estrogen Receptor alpha Estrogens Etiology Exhibits Fatty Acids Female Gene Expression Generations Genes Genetic Transcription Hepatic Hepatocarcinogenesis Hepatocyte High Fat Diet Histologic Histone Acetylation Histone Deacetylase Human Incidence Inflammation Isoenzymes Knock-out Knockout Mice Link Lipids Liver Liver Mitochondria Malignant neoplasm of liver Mediating Metabolic Mitochondria Modeling Molecular Mus Nuclear Obesity Oncogenic Organelles Oxidative Stress Pathway interactions Patients Physiological Play Predisposition Primary carcinoma of the liver cells Production Prognosis Publishing Reactive Oxygen Species Regulation Reporting Resistance Respiration Risk Rodent Role Sex Differences Signal Pathway Signal Transduction Signaling Protein Sphingolipids Structure Techniques Testing Testosterone Triglycerides Water Woman c-myc Genes gene repression high risk human disease inhibitor intrahepatic liver cell proliferation male men mitochondrial dysfunction mortality non-alcoholic fatty liver disease nonalcoholic steatohepatitis novel personalized medicine premalignant prohibitin respiratory sex sexual dimorphism sexual disparity sphingosine 1-phosphate sphingosine kinase stem cells sugar transcriptomics treatment strategy tumor tumor initiation tumorigenesis

项目摘要

PROJECT SUMMARY Hepatocellular carcinoma (HCC) is the third leading cause of cancer related deaths worldwide and its incidence is increasing due to endemic obesity. Sexual dimorphism exists in HCC incidence as women have a significantly lower risk for developing HCC than men. However, the molecular mechanisms of HCC sexual dimorphism remain unclear, hindering development of better therapies for this disease. This proposal will utilize a new model that we developed of diet-induced progression of NASH to HCC that recapitulates key physiological, metabolic, histologic and transcriptomic changes observed in the human disease to examine previously unrecognized roles of sphingosine kinase 2 (SphK2), an enzyme that regulates the balance of bioactive sphingolipid metabolites, sphingosine-1-phosphate (S1P) and ceramide, in sexual dimorphism of HCC. Similar to humans, we found that on this diet, wild-type male mice, but not females, develop HCC. Strikingly, SphK2 knockout male mice have reduced tumor incidence, whereas in females, liver cancer developed only in SphK2 knockout mice. Thus, we propose that SphK2 plays a critical role in sexual dimorphism of HCC. We will test the central hypothesis that SphK2 protects females from HCC, while promoting it in males through several mutually non-exclusive mechanisms in distinct hepatic subcellular organelles. Aim 1 will examine the role of liver SphK2 in key signaling pathways that promote HCC in males and Aim 2 will define the role of SphK2 in nuclear and mitochondrial mechanisms mediating resistance of females to HCC. Our proposal utilizes a unique animal model and state-of-the-art techniques to identify novel SphK2-regulated molecular mechanisms involved in sexual disparity in diet-induced progression of NASH to HCC, and also has translational implications for the use of SphK2 inhibitors now in clinical trials. This study will lead to better understanding of sex differences in HCC important for personalized treatment strategies for this devastating disease.

项目总结