Hormonal control of NASH development and progression

NASH 发生和进展的激素控制

• 批准号: 10588460
• 负责人: Rhonda D Kineman
• 金额: --
• 依托单位: JESSE BROWN VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10588460
• 关键词: Acute; Adult; Age; Androgens; Boston; Breast Cancer Risk Factor; Cardiovascular Diseases; Caring; Cells; Cirrhosis; Clinical; Collaborations; Coupled; Data; Development; Diabetes Mellitus; Diet; Disease; Disease Progression; Drug Targeting; Endothelium; Environmental Risk Factor; Estrogen Receptors; Estrogens; Etiology; Female; Feminization; Fibrosis; Future; Gene Expression; General Population; Genetic; Genomics; Growth Hormone Receptor; Health; Hepatic; Hepatocyte; Hormonal; Hormone secretion; Hypothalamic structure; IGF1 gene; Immune; Inflammation; JAK2 gene; Knowledge; Lipids; Literature; Liver; Liver Failure; Malignant neoplasm of liver; Mediating; Metabolism; Mus; Outcome; Pathology; Patients; Pattern; Pharmaceutical Preparations; Phenotype; Physiology; Pituitary Gland; Play; Population; Postmenopause; Primary carcinoma of the liver cells; Production; Protein Hormone Receptor; Publishing; Regulation; Role; Severities; Signal Transduction; Somatotropin; Symptoms; Tamoxifen; Techniques; Technology; Testing; Tissue-Specific Gene Expression; Tissues; Translating; Universities; Veterans; Western Blotting; Woman; Women' s Health; Work; Xenobiotics; cardiovascular risk factor; cell type; cholangiocyte; constitutive expression; diabetic patient; drug clearance; feeding; heart disease risk; high risk; improved; innovation; insight; knock-down; male; malignant breast neoplasm; men; mouse model; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; obese patients; prevent; protective effect; receptor; receptor-mediated signaling; reproductive; reproductive axis; response; sex; sexual dimorphism; simple steatosis; single nucleus RNA-sequencing; transcriptome sequencing

Abstract/Summary Non-alcoholic fatty liver disease (NAFLD) includes a spectrum of pathologies ranging from simple steatosis to non-alcoholic steatohepatitis (NASH – steatosis, hepatocyte ballooning and inflammation, with or without fibrosis). Highly prevalent in obese and diabetic patients, NASH is an independent risk factor for cardiovascular disease, cirrhosis, and hepatocellular carcinoma, devastating diseases that are more prevalent in veterans than in the general population. Women of reproductive age have lower rates of NASH; however, this protection is lost after menopause when NASH rates equal or exceed those for men. Both clinical and experimental data indicate that estrogen plays a major role in protecting women against NASH. Moreover, the protective effects of estrogen may also extend to men via tissue-dependent aromatization of androgens to estrogens. Despite this knowledge, the precise tissue-specific mechanisms for estrogen-mediated protection have not been directly investigated. This proposal will focus on the interrelationship between estrogen and growth hormone (GH), specifically at the level of the hepatocyte, where published literature and preliminary data generated by our group have led to the HYPOTHESIS that the estrogen receptor, ER, as well as the GH receptor (GHR), are required to slow NASH development in part by sustaining hepatocyte Stat5b activity. Studies will compare male and female mice with adult-onset, hepatocyte-specific, knockdown of the estrogen receptor, ER or GHR alone, or in combination to: SA1 Determine the role of ER in hepatocyte Stat5b action and its impact on hepatic function and physiology in the presence and absence of GHR-mediated signaling; SA2 Determine if hepatocyte ER protects against diet- induced NASH, in the presence and absence of GHR; SA3 Determine if hepatocyte ER and/or GHR play a role in tamoxifen (TAM) induced NASH progression. Endpoint analysis includes assessment of 1) GH-axis function, whole body metabolism, liver lipid content and pathology, 2) Hepatic response to acute GH challenge (western blot analysis of downstream intracellular signals and 3) Hepatic cell-type specific gene expression using single nuclei RNA-Seq (snRNA-Seq), a technique that provides important information on the potential crosstalk between cell types within the liver, critical for NASH development. The outcomes of this project will generate new mechanistic insights to identify future drug targets to prevent NASH progression in both male and female veterans.

摘要/摘要 非酒精性脂肪肝疾病（NAFLD）包括一系列病理，从简单的脂肪变性也 非酒精性脂肪植物（Nash Steatosis，肝细胞气球和炎症，有或没有或没有或没有 纤维化）。 疾病，肝硬化和肝细胞癌，毁灭性疾病在退伍军人thans中更多。 在一般的poption中。 更年期后，纳什对男人的评分相等或分配给男性。 该雌激素在保护女性免受纳什的保护方面起着重要作用。 尽管有这些知识，也可以通过组织依赖性雄激素扩展到男性。 尚未直接研究用于雌激素介导的保护的精确组织特异性机制。 该提案将重点介绍雌激素和生长激素（GH）之间的相互攻击，特定于您 肝细胞的水平，整个出版的文献和我们小组产生的初步数据导致了 假设雌激素受体ER以及GH受体（GHR）是需要慢速NASH的假设 部分通过肝细胞STAT5B活动的部分发展将与男性和雌性小鼠与。 成人发作，肝细胞规定，单独使用ER或GHR的敲低，或组合： SA1确定ER在肝细胞STAT5B作用中的作用及其对肝脏和生理学的影响 GHR介导的信号的存在和不存在； 在GHR的存在和不存在的情况下，诱导的NASH； 在他莫昔芬（TAM）中，诱导了纳什进度。 全身代谢，肝脂质含量和病理学，2）肝反应急性GH挑战（Westernn 下游细胞内信号的印迹分析和3）使用单个的肝细胞型特异性基因表达 核RNA-Seq（SnRNA-Seq），一种有关潜在crostalk的重要信息 在肝脏内的细胞类型之间，对NASH开发至关重要。 新的机械见解，以确定男性和女性的未来药物纳什进展的未来药物目标 退伍军人。