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 非酒精性脂肪肝病 (NAFLD) 是全世界肝病的最常见原因；进展到 非酒精性脂肪性肝炎 (NASH) 肝硬化发生在部分患者中，是第二个主要适应症 在美国进行肝移植。导致 NAFLD 发生和进展的因素 对非酒精性脂肪性肝炎（NASH）的影响，包括炎症和纤维化，人们知之甚少。而且， 这些疾病缺乏有效的治疗方法。对动物和人类的研究表明，雌激素 缺乏可能是 NAFLD 发生和进展为 NASH 的重要机制。 然而，尚无前瞻性、随机、安慰剂对照研究检验雌激素的影响 治疗患有 NASH 的绝经后妇女的脂肪变性、炎症或纤维化。我们的整体 假设是低剂量、透皮雌激素给药会减少肝脏脂肪、炎症和 经活检证实患有 NASH 的女性会出现纤维化。此外，我们将探讨雌激素的免疫和代谢作用 肝脏中的变化，包括单细胞水平的变化。目标 1 将检验雌二醇给药的假设 将减少经活检证实患有 NASH 的女性的纤维化、炎症和脂肪变性。目标 2 将确定 雌激素对肝内代谢途径和肝内转录景观的影响 免疫细胞。我们假设雌激素会减少纤维生成，减少肝脏从头脂肪生成， 并增加脂质β氧化。这些假设将通过严格设计的、双盲的、 低剂量经皮雌激素替代疗法效果的安慰剂对照研究 患有 NASH 的绝经后妇女。最先进的肝脏成像、肝脏活检、全肝脏转录组学和 SeqWell 的无偏单细胞 RNAseq 将用于研究这些假设。我们已经集合了 一个由在内分泌学（Miller 博士）、NAFLD（Corey 博士）方面拥有丰富研究经验的研究人员组成的团队， 肝脏成像（Bredella 博士）和肝脏免疫学（Lauer 博士）在开展这项研究方面具有独特的优势 多学科提案。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治疗靶点。