Estrogen Administration for the Treatment of NASH in Postmenopausal Women

雌激素治疗绝经后妇女 NASH

• 批准号: 10307423
• 负责人: Miriam Antoinette Bredella
• 金额: $ 73.37万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10307423
• 关键词: ADD-1 protein; Age; Animals; Biopsy; CD8-Positive T-Lymphocytes; Cell Lineage; Cells; Characteristics; Cirrhosis; Data; Development; Disease; Disease Progression; Dose; Double-Blind Method; ECM receptor; Endocrinology; Epidemic; Estradiol; Estrogen Replacement Therapy; Estrogen Therapy; Estrogens; FDA approved; Fatty acid glycerol esters; Fibrosis; Gene Expression Profile; Generations; Genes; Genetic Transcription; Gold; Hepatic; High Prevalence; Human; IL17 Signaling Pathway; Immune; Immunologics; Immunology; Inflammation; Lipids; Liver; Liver Fibrosis; Liver diseases; Lobular; Low Prevalence; Machine Learning; Magnetic Resonance Spectroscopy; Manipulative Therapies; Menopause; Metabolic; Metabolic Diseases; Metabolic Pathway; Methods; Microscopy; Obesity; Ovariectomy; Pathogenesis; Pathologic; Pathway interactions; Placebos; Play; Positioning Attribute; Postmenopause; Pre-Clinical Model; Premenopause; Prevalence; Prevention trial; Process; Prospective Studies; Protons; Randomized; Rattus; Research; Research Personnel; Risk; Role; Secondary to; Technology; Testing; Tissues; United States; Woman; Work; clinically significant; design; double-blind placebo controlled trial; effective therapy; elastography; experience; fibrogenesis; immunoregulation; improved; intrahepatic; lipid biosynthesis; liver biopsy; liver imaging; liver transplantation; macrophage; men; multidisciplinary; new therapeutic target; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; oxidation; patient subsets; placebo controlled study; primary endpoint; prospective; randomized placebo controlled study; response; second harmonic; sex; single-cell RNA sequencing; therapy development; transcriptome sequencing; transcriptomics; transdermal estrogen

PROJECT ABSTRACT Non-alcoholic fatty liver disease (NAFLD) is the most common cause of liver disease worldwide; progression to non-alcoholic steatohepatitis (NASH) cirrhosis occurs in a subset of patients and is the second leading indication for liver transplantation in the United States. The factors leading to the development of NAFLD and progression to nonalcoholic steatohepatitis (NASH), including inflammation and fibrosis, are poorly understood. Moreover, there is a lack of effective therapies for these disorders. Studies in animals and humans suggest that estrogen deficiency may be an important mechanism underlying the development of NAFLD and progression to NASH. However, no prospective, randomized, placebo-controlled studies have examined the impact of estrogen administration on steatosis, inflammation or fibrosis in postmenopausal women with NASH. Our overall hypothesis is that low-dose, transdermal estrogen administration will decrease hepatic fat, inflammation and fibrosis in women with biopsy-proven NASH. Further, we will explore estrogen’s immune and metabolic effects in the liver, including changes at the single-cell level. Aim 1 will test the hypothesis that estradiol administration will decrease fibrosis, inflammation and steatosis in women with biopsy-proven NASH. Aim 2 will determine the impact of estrogen on intrahepatic metabolic pathways and on the transcriptional landscape of intrahepatic immune cells. We hypothesize that estrogen will decrease fibrogenesis, decrease hepatic de novo lipogenesis, and increase lipid beta oxidation. These hypotheses will be tested with a rigorously designed, double-blind, placebo-controlled study of the effects of low-dose transdermal estrogen replacement therapy in postmenopausal women with NASH. State-of-the-art liver imaging, liver biopsies, whole liver transcriptomics and unbiased single cell RNAseq by SeqWell will be leveraged to investigate these hypotheses. We have assembled a team of investigators with extensive research experience in endocrinology (Dr. Miller), NAFLD (Dr. Corey), liver imaging (Dr. Bredella), and hepatic immunology (Dr. Lauer), which is uniquely positioned to carry out this multi-disciplinary proposal. Elucidating the effects of low-dose, transdermal estrogen administration on liver fibrosis, inflammation and steatosis has the potential to further our understanding of this disease process and identify new therapeutic targets where few currently exist.

项目摘要 非酒精性脂肪性肝病（NAFLD）是全球肝病最常见的原因;进展至 非酒精性脂肪性肝炎（NASH）肝硬化发生在一部分患者中，是第二大适应症 在美国进行肝移植。导致NAFLD发展和进展的因素 非酒精性脂肪性肝炎（NASH），包括炎症和纤维化，知之甚少。此外，委员会认为， 对于这些疾病缺乏有效的治疗方法。对动物和人类的研究表明， 缺乏可能是NAFLD发展和进展为NASH的重要机制。 然而，没有前瞻性的，随机的，安慰剂对照的研究已经检查了雌激素的影响 在患有NASH的绝经后妇女中，给药对脂肪变性、炎症或纤维化的影响。我们的整体 有一种假说认为，低剂量经皮雌激素给药将减少肝脏脂肪、炎症和 在活检证实的NASH女性中的纤维化。此外，我们将探讨雌激素的免疫和代谢作用 包括单细胞水平的变化。目的1将检验雌二醇给药 将减少活检证实的NASH女性的纤维化、炎症和脂肪变性。目标2将决定 雌激素对肝内代谢途径和肝内转录水平的影响 免疫细胞我们假设雌激素会减少肝纤维化，减少肝脏新生脂肪生成， 增加脂质β氧化。这些假设将通过严格设计的双盲， 低剂量经皮雌激素替代疗法对乳腺癌的疗效的安慰剂对照研究 患有NASH的绝经后妇女。最先进的肝脏成像、肝脏活检、全肝转录组学和 将利用SeqWell的无偏单细胞RNAseq来研究这些假设。我们已经组建 一组在内分泌学（米勒博士）、NAFLD（科里博士）、 肝脏成像（Bredella博士）和肝脏免疫学（劳尔博士），这是独特的定位，以执行这一点 多学科的建议。阐明低剂量经皮雌激素给药对肝脏的影响 纤维化、炎症和脂肪变性有可能进一步加深我们对这种疾病过程的理解， 确定目前很少存在的新的治疗靶点。