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

• 批准号: 10268997
• 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
• 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/10268997
• 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 trial

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.

摘要 尽管临床结果不佳，但针对肝脏炎症的治疗反应非常有限 特别是营养不良的患者。肌肉减少症或骨骼肌损失是 AH中的营养不良并对这些患者的临床结果产生不利影响。中的可能作用 肌肉减少症可加重AH，包括骨骼肌乙醇代谢减少和氨受损 由于肝尿素生成减少而导致的处置促进氨诱导的肝毒性。即使 靶向肌肉减少症是一种具有机械原理的创新方法，可改善 啊，这不是正在进行的NIAAA资助的AlcHep网络的治疗策略的一部分。我们的出版和 初步数据显示，响应于乙醇，骨骼肌蛋白质稳态或蛋白质稳态失调 在肌管、小鼠模型和患有酒精性肝病（包括AH）的人类患者中。我们还观察到 乙醇暴露会增加骨骼肌对脂多糖（LPS）的敏感性， 蛋白质合成受损和自噬增加以及随之发生的肌肉减少症。有趣的是， 典型的LPS受体TLR4在暴露于乙醇的小鼠的肌管和肌肉中增加， 酒精性肝病患者。同样，TLR4的下游靶点P65NFkB被激活， 增加TGFβ超家族成员、P65NFkB的已知转录靶点肌生成抑制素的表达 LPS和乙醇也可增加骨骼肌蛋白质合成的负调节因子。有趣的是， 低分子量的透明质酸，特别是35Kd和更低的片段（HA35）已被报道抑制 或以环境特异性方式通过特异性受体调节TLR4信号传导。我们做了一个新的观察 HA35逆转了乙醇和LPS诱导的肌管直径减小，破坏了蛋白质稳态和信号传导， 肌管和暴露于乙醇的小鼠中的扰动。我们将使用HA35最初在肌管暴露于 酒精和小鼠长期喂食酒精与狂欢（高模型），具有显着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 HA35逆转AH中的肌肉减少症。我们将研究乙醇喂养小鼠对HA35的组织反应，包括 骨骼肌蛋白质合成和分解以及信号应答。我们将翻译我们的初步和 通过用HA35（一种食品补充剂）治疗人类受试者，将急性炎症后的临床前数据转化为临床应用， 酒精暴露我们还将测试HA35是否对中度AH患者有益， 尽管有显著的肌肉损失，但目前没有可用的治疗方法，并且没有正在进行的临床研究。 Alchep网络中中度AH的试验。一个数据协调中心将协助这些人类研究。 这些研究将允许我们的研究使用HA35作为一种新的，基于机制的治疗转化。 AH中肌肉减少症的治疗，目前这是该患者人群中未满足的主要需求。