Novel mechanism based treatment to improve tissue injury in alcoholic hepatitis

改善酒精性肝炎组织损伤的新机制治疗

基本信息

批准号：
10456629
负责人：
Srinivasan Dasarathy
金额：
$ 55.78万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-25 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10456629
关键词：
Acute Affect Alcoholic Hepatitis Alcoholic Liver Diseases Alcohols Ammonia Autophagocytosis Binding CD14 Antigen CD44 Antigens CD44 gene Caliber Cell Culture Techniques Chronic Clinical Clinical Trials Data Data Coordinating Center Development Endotoxemia Ethanol Ethanol Metabolism Food Supplements Funding GDF8 gene Genetic Transcription Goals Hepatic Hepatocyte Hepatotoxicity Human Hyaluronan Hyaluronic Acid Hyperammonemia Impairment In Vitro Inflammation Inflammatory Response Injury Knowledge Kupffer Cells Life Lipopolysaccharides Liver Liver diseases Malnutrition Mediating Mediator of activation protein Metabolic Modeling Molecular Molecular Weight Morbidity - disease rate Mus Muscle Muscle Fibers Muscular Atrophy National Institute on Alcohol Abuse and Alcoholism Oral Organ Outcome Pathway interactions Patients Pharmacotherapy Physiological Play Polymers Polysaccharides Preparation Prevention Protein Biosynthesis Publishing Receptor Signaling Reporting Role Signal Pathway Signal Transduction Skeletal Muscle TLR4 gene Testing Therapeutic Tissues Toll-like receptors Transforming Growth Factor beta Translating Translations alcohol effect alcohol exposure alcohol response base circulating biomarkers clinical application clinically significant gain of function gastrointestinal epithelium hepatic ureagenesis hepatocyte injury human subject improved improved outcome in vivo innovation intestinal epithelium liver injury member mortality mouse model muscle form muscle hypertrophy novel nutritional supplementation patient population pre-clinical preclinical study prevent problem drinker proteostasis receptor response sarcopenia satellite cell skeletal muscle metabolism skeletal muscle wasting targeted treatment therapeutic target tissue injury treatment response treatment trial

项目摘要

Abstract Despite poor clinical outcomes there has been very limited response to therapies targeting hepatic inflammatory response especially in patients with malnutrition. Sarcopenia or skeletal muscle loss is a major component of malnutrition in AH and adversely affects clinical outcomes in these patients. Potential mechanisms by which sarcopenia can aggravate AH include reduced skeletal muscle metabolism of ethanol and impaired ammonia disposal due to decreased hepatic ureagenesis promoting ammonia induced hepatotoxicity. Even though targeting sarcopenia is an innovative approach with a mechanistic rationale to improve outcomes in patients with AH, this is not part of the therapeutic strategy in the ongoing NIAAA funded AlcHep network. Our published and preliminary data show dysregulated skeletal muscle protein homeostasis or proteostasis in response to ethanol in myotubes, mouse models, and human patients with alcoholic liver disease including AH. We also observed that ethanol exposure increases the skeletal muscle sensitivity to lipopolysaccharide (LPS) that results in impaired protein synthesis and increased autophagy and consequent sarcopenia. Interestingly, expression of canonical LPS receptor, TLR4, is increased in myotubes and in muscles from mice exposed to ethanol and patients with alcoholic liver disease. Consistently, P65NFkB, a downstream target of TLR4, is activated with increased. Expression of myostatin, a TGFβ superfamily member, a known transcriptional target of P65NFkB and negative regulator of skeletal muscle protein synthesis is also increased with LPS and ethanol. Interestingly, low molecular weight hyaluronic acid, especially fragments 35Kd and lower (HA35) have been reported to inhibit or modulate TLR4 signaling via specific receptors in a context specific manner. We made a novel observation that HA35 reversed ethanol and LPS induced reduction in myotube diameter, impaired proteostasis and signaling perturbations in both myotubes and mice exposed to ethanol. We will use HA35 initially in myotubes exposed to ethanol and mice chronically fed ethanol with binge (Gao model) that has significant sarcopenia and liver injury similar to that in human AH. In these preclinical studies, we will determine the molecular mechanisms by which HA35 reverses sarcopenia in AH. We will study the tissue responses to HA35 in ethanol-fed mice including skeletal muscle protein synthesis and breakdown and signaling responses. We will translate our preliminary and preclinical data into clinical application by treating human subjects with HA35, a food supplement, following acute ethanol exposure. We will also test if HA35 is beneficial in patients with moderate AH, a group of patients for whom there are currently no therapies available despite significant muscle loss and there are no ongoing clinical trials in moderate AH in the Alchep network. A data coordinating center will assist with these human studies. These studies will permit rapid therapeutic translation of our studies using HA35 as a novel, mechanism-based therapy for sarcopenia in AH, currently a major unmet need in this patient population.

抽象的尽管临床结果不佳，但针对肝脏炎症的治疗反应非常有限反应尤其是营养不良的患者中，肌肉减少症或骨骼肌丧失是一个主要组成部分。 AH 营养不良并对这些患者的临床结果产生不利影响的潜在机制。肌肉减少症会加重 AH，包括骨骼肌对乙醇的代谢减少和氨受损由于肝脏尿素生成减少，促进氨诱导的肝毒性。针对肌肉减少症是一种创新方法，具有改善肌肉减少症患者预后的机制原理啊，这不是 NIAAA 资助的 AlcHep 网络的治疗策略的一部分。初步数据显示，乙醇导致骨骼肌蛋白稳态或蛋白质稳态失调我们还在肌管、小鼠模型和患有酒精性肝病（包括 AH）的人类患者中观察到了这一现象。乙醇暴露会增加骨骼肌对脂多糖（LPS）的敏感性，从而导致蛋白质合成受损、自噬增加以及随之而来的肌少症。暴露于乙醇和乙醇的小鼠的肌管和肌肉中典型的 LPS 受体 TLR4 增加与酒精性肝病患者一样，TLR4 的下游靶标 P65NFkB 也被激活。肌生长抑制素（TGFβ 超家族成员）的表达增加，是 P65NFkB 的已知转录靶标。 LPS 和乙醇也可增加骨骼肌蛋白质合成的负调节作用。据报道，低分子量透明质酸，特别是 35Kd 及以下片段 (HA35) 可以抑制或通过特定受体以特定方式调节 TLR4 信号传导我们进行了一项新颖的观察。 HA35 逆转乙醇和 LPS 诱导的肌管直径减小、蛋白质稳态和信号传导受损我们将首先在暴露于乙醇的肌管中使用 HA35。乙醇和长期暴食乙醇的小鼠（Gao模型）会出现明显的肌肉减少症和肝损伤与人类 AH 相似，在这些临床前研究中，我们将确定其分子机制。 HA35 逆转 AH 中的肌肉减少症我们将研究乙醇喂养的小鼠中对 HA35 的组织反应，包括我们将翻译我们的初步和信号反应。通过使用HA35（一种食品补充剂）治疗急性发作后的人类受试者，将临床前数据转化为临床应用我们还将测试 HA35 对中度 AH 患者（一组患有中度 AH 的患者）是否有益。尽管肌肉明显丧失，但目前尚无可用的治疗方法，并且没有正在进行的临床治疗 Alchep 网络中的中度 AH 试验将由数据协调中心协助进行这些人体研究。这些研究将允许我们使用 HA35 作为一种新颖的、基于机制的研究快速进行治疗转化。治疗 AH 中的肌肉减少症，目前是该患者群体中一个未满足的主要需求。