Sexual dimorphism of acetaminophen-induced liver injury and regeneration

对乙酰氨基酚诱导的肝损伤和再生的性别二态性

基本信息

批准号：
10315150
负责人：
Elissa Everton
金额：
$ 4.6万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10315150
关键词：
Acceleration Acetaminophen Acute Liver Failure Address Albumins American Aminophenols Analgesic and Antipyretic Analgesics Anti-Inflammatory Agents Architecture Automobile Driving Binding Biological Biological Assay CYP2E1 gene Cell Cycle Cell Death Cells Clinic Clinical Consumption Country Cysteine Cytochromes Data Detection Dose Effectiveness Endothelial Cells Female Foundations Glutathione Goals Gonadal Steroid Hormones Growth Hormone Receptor Hepatocyte Hepatotoxicity Hormone secretion Hormones Hour Imines Inflammatory Injections Injury Intoxication Knock-out Literature Liver Liver Failure Liver Regeneration Liver diseases Mediating Metabolic Metabolic Pathway Mus Natural regeneration Organ Overdose Pathway interactions Pharmaceutical Preparations Preparation Process Receptor Activation Recovery Resistance Role Serum Somatotropin Testing Therapeutic Therapeutic Effect Time Tissues Toxic effect Treatment Efficacy United States acetaminophen overdose alternative treatment cadherin 5 cell type differential expression exhaust hepatic necrosis hormone therapy injury and repair liver injury liver repair liver transplantation male necrotic tissue novel therapeutic intervention para-benzoquinone receptor regenerative restoration sex sexual dimorphism sexual disparity single-cell RNA sequencing standard care standard of care tissue repair treatment comparison urinary

项目摘要

ABSTRACT Acetaminophen (acetyl-para-aminophenol or APAP) is the most commonly used pain reliever in the United States, yet acetaminophen overdose is the leading cause of acute liver failure in the developed world. Currently the only available treatments are N-acetyl cysteine (NAC), which only has a short window of effectiveness, or ultimately liver transplant. Therefore, therapeutic alternatives to treat APAP overdose are urgently needed in the clinic. This proposal will address this issue by deciphering the mechanisms of sexual dimorphism of APAP-induced liver injury and repair, and to leverage this sexual dimorphism by establishing how hormone therapy will accelerate liver recovery in both sexes following APAP overdose. Sex hormones and their receptors have been implicated in driving sexual dimorphism in many liver processes. Specifically, higher average levels of growth hormone (GH) secretion in females contributes to higher metabolic activity in their livers. Consistent with the literature, our preliminary data support the higher resistance of female mice to APAP, shown by reduced liver necrosis, cell death, and detection of serum injury markers compared to males. Moreover, our single-cell RNA sequencing analyses reveal that female hepatocytes and endothelial cells (ECs) express significantly higher levels of GH receptor and GH pathway activation than male cells, while males have upregulated inflammatory and cell death pathway activation. In preparation for this application, we generated preliminary data showing that GH treatment significantly and rapidly repairs the tissues of both males and females following sub-lethal doses of APAP, as quantified by tissue necrosis, cell death, and mouse survival. These key data suggest a sexually dimorphic liver regenerative advantage in females, which can be recapitulated with GH treatment to induce recovery in males and accelerate recovery in females. Therefore, we hypothesize that there is a sexual dimorphism in APAP sensitivity that we can leverage with the use of GH to accelerate liver regeneration in both sexes. In this proposal, we will further examine the role of GH and its pathway activation in hepatocytes and ECs following APAP overdose via single-cell RNA sequencing analysis and hepatocyte and EC -specific GH receptor knockouts. We will leverage these findings to establish an optimal GH therapy with identification of GH specific doses and time frame of effectiveness for each sex to mitigate liver injury and accelerate liver regeneration with superior efficacy to the current standard-of-care NAC. Potential additive therapeutic effect of combined GH/NAC treatment will be also determined. In conclusion, understanding the biological mechanisms behind the sexual disparity in APAP-induced liver injury, subsequent regeneration, and modulation by GH will provide the biological foundation to establish a GH therapy to treat APAP overdose in both sexes, a currently unmet clinical need.

抽象的对乙酰氨基酚（乙酰对氨基苯酚或 APAP）是最常用的止痛药在美国，但对乙酰氨基酚过量是发达国家急性肝衰竭的主要原因。目前唯一可用的治疗方法是 N-乙酰半胱氨酸 (NAC)，其作用窗口很短。效果，或者最终是肝移植。因此，治疗 APAP 过量的治疗替代方案是临床上急需。该提案将通过破译机制来解决这个问题 APAP 诱导的肝损伤和修复的性别二态性，并通过以下方式利用这种性别二态性：确定激素治疗如何加速 APAP 过量后两性的肝脏恢复。性激素及其受体与许多肝脏过程中性别二态性的驱动有关。具体来说，女性生长激素 (GH) 分泌的平均水平较高，导致新陈代谢较高他们肝脏的活动。与文献一致，我们的初步数据支持女性的抵抗力较高与小鼠相比，APAP 小鼠的肝坏死、细胞死亡和血清损伤标志物检测减少男性。此外，我们的单细胞 RNA 测序分析表明，雌性肝细胞和内皮细胞 (EC) 表达的 GH 受体和 GH 通路激活水平显着高于雄性细胞，而雄性细胞上调炎症和细胞死亡途径的激活。为了准备这个应用程序，我们生成的初步数据显示 GH 治疗显着且快速地修复了雄性的组织雌性小鼠在接受亚致死剂量的 APAP 后，通过组织坏死、细胞死亡和小鼠存活进行量化。这些关键数据表明雌性的性别二态性肝脏再生优势，可以概括一下使用 GH 治疗可诱导男性康复并加速女性康复。因此，我们假设 APAP 敏感性存在性别二态性，我们可以通过使用 GH 来利用它加速两性的肝脏再生。在本提案中，我们将进一步探讨 GH 的作用及其通过单细胞 RNA 测序分析 APAP 过量后肝细胞和 EC 中的通路激活以及肝细胞和 EC 特异性 GH 受体敲除。我们将利用这些发现来建立一个最佳的 GH 疗法，确定 GH 特定剂量和每个性别的有效时间范围，以减轻肝脏负担损伤并加速肝再生，其疗效优于当前护理标准 NAC。潜在的还将确定联合 GH/NAC 治疗的附加治疗效果。综上所述，了解 APAP 引起的肝损伤中性别差异背后的生物学机制，随后 GH 的再生和调节将为建立 GH 疗法提供生物学基础，以治疗两性 APAP 过量，目前临床需求尚未得到满足。