BEASTS-Novel Biomimetic Liver Platform for Enabling ALD Researchers

BEASTS-为 ALD 研究人员提供支持的新型仿生肝脏平台

• 批准号: 10697452
• 负责人: SRIVATSAN S KIDAMBI
• 金额: $ 38.51万
• 依托单位: KESHAVA BIOSCIENCES LLC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10697452
• 关键词: Address; Adhesives; Albumins; Alcohol consumption; Alcohol dehydrogenase; Alcohol-Induced Disorders; Alcoholic Fatty Liver; Alcoholic Hepatitis; Alcoholic Liver Cirrhosis; Alcoholic Liver Diseases; Alcohols; Animal Model; Animal Testing Alternatives; Bile Acids; Biological Sciences; Biomedical Engineering; Biomimetics; CYP2E1 gene; Cell Communication; Cell Line; Cells; Chronic; Cirrhosis; Clinical; Clinical Data; Coculture Techniques; Collaborations; Complex; Cues; Data; Detection; Development; Disease; Disease Progression; Disease model; Drug Combinations; Drug Screening; Elements; Engineering; Environment; Ethanol; Ethanol Metabolism; Ethics; Exhibits; Experimental Models; Failure; Fatty acid glycerol esters; Fibrosis; Foundations; Gene Expression; Generations; Goals; Grant; Growth; Hepatic; Hepatic Stellate Cell; Hepatocyte; Human; In Situ; In Vitro; Injury; Investigation; Length; Liver; Liver Fibrosis; Liver Stem Cell; Liver diseases; Maintenance; Marketing; Measures; Mechanics; Metabolic; Methodology; Modeling; Molecular; Morbidity - disease rate; National Institute on Alcohol Abuse and Alcoholism; Organoids; Outcome; Outcome Study; Oxidation-Reduction; Pathologic; Pathology; Patients; Pharmacogenetics; Pharmacologic Substance; Phase; Phenotype; Physiological; Physiology; Prevalence; Preventive; Primary carcinoma of the liver cells; Production; Rapid screening; Reaction; Reporting; Research Personnel; Signal Transduction; Siloxanes; Small Business Innovation Research Grant; Staging; System; Technology; Testing; Therapeutic Effect; Time; Urea; Validation; Western Blotting; alcohol effect; alcohol exposure; chronic liver disease; clinically relevant; design; drug candidate; drug development; effective therapy; experimental study; high-throughput drug screening; improved; in vitro Model; induced pluripotent stem cell; interest; liver stiffness; liver transplantation; mechanical signal; mortality; new therapeutic target; novel; pharmacologic; phase 1 study; precision drugs; preservation; prevent; prognostic indicator; research clinical testing; response; simple steatosis; stellate cell; success; tool; uptake

PROJECT SUMMARY Alcoholic liver disease (ALD) is one of the major causes of morbidity and mortality in the world. Significant challenges remain for developing preventive or curative approaches targeting ALD. No effective treatments for ALD currently exist but for reducing alcohol consumption or liver transplantation. The current paucity of clinically relevant experimental models impedes any effort to identify ALD prognostic indicators and potential effective treatment options. It has been challenging to develop an animal model that exhibits severe alcohol- induced injury such as fibrosis or cirrhosis. Biomimetic in vitro models are urgently needed to allow both investigation of the mechanisms of liver fibrosis and higher-throughput screening of drugs and drug combinations that decrease liver fat accumulation and/or prevent the generation of a fibrotic reaction to steatosis. While some in vitro platforms have recently reported the development of more pathologically relevant liver models, their methodology lacks both dynamic (mechanical) cues that might improve the model relevance and in situ bioanalysis capacity, limiting their possible integration with personalized drug screening. Also, though some of these platforms shown maintenance of several key hepatocyte differentiated function in vitro, none of these platforms have demonstrated alcohol dehydrogenase (ADH) and CYP2E1 expression/activity for sustained periods which are critical for alcohol metabolism and for studying ALD. This limitation is particularly noteworthy since these elements are critical to the development of ALD. The overall goal of Keshava Biosciences LLC is to develop a novel biomimetic liver model closely mimicking the hepatic environment in physiologic and pathological conditions enabled by microtechnology. Keshava Biosciences LLC in collaboration with Dr. Kidambi (CEO and bioengineer with expertise in biomimetic liver models) has pioneered the use of biomimetic “BEASTS (Bio-Engineered Adhesive Siloxane substrate with Tunable Stiffness)” platform, which enables preserving primary human hepatocytes (PHHs) including liver- specific synthetic functions (urea and albumin production; bile acid uptake), maintaining ADH and CYP2E1 activity for 10 days. BEASTS platform uniquely recreates the physiologic (2 kPa) and pathologic liver stiffness at various stages of ALD (8, 15, 25, 55 kPa) to allow mimicking fibrosis in ALD patients which is lacking in current animal models. The model will be optimized in 3 steps: optimization of the mechanical insult, optimization of the injury phenotype and optimization of the therapeutic effect of positive control compounds. These tools hold the promise of incremental clinical success in place of the status quo of total clinical failure. Ultimately, this disruptive technology will enable the rapid screening of pharmacological compounds for beneficial or detrimental effects on ALD and for the detection of pharmacogenetic interactions. This also aligns well with NIAAA interests- (i) Development and validation of tools, models, and technologies; (ii) Development of drug candidates for treating ALD.

项目摘要 酒精性肝病（ALD）是世界范围内发病和死亡的主要原因之一。显著 开发针对ALD的预防或治疗方法仍然存在挑战。没有有效的治疗方法 ALD目前存在，但用于减少酒精消耗或肝移植。目前缺乏 临床相关的实验模型阻碍了确定ALD预后指标和潜在的 有效的治疗选择。开发一种表现出严重酒精中毒的动物模型一直是具有挑战性的- 引起的损伤，如纤维化或肝硬化。迫切需要仿生体外模型， 肝纤维化发生机制的研究及药物的高通量筛选 减少肝脏脂肪积累和/或防止纤维化反应的产生的组合， 脂肪变性虽然一些体外平台最近报道了更多病理相关的发展， 肝脏模型，他们的方法缺乏可能改善模型相关性的动态（机械）线索 和原位生物分析能力，限制了它们与个性化药物筛选的可能整合。还有， 尽管这些平台中的一些在体外显示出几种关键的肝细胞分化功能的维持， 这些平台均未证明乙醇脱氢酶（ADH）和CYP 2 E1 持续的表达/活性对于酒精代谢和研究至关重要 ALD。这种限制是特别值得注意的，因为这些元素对ALD的发展至关重要。的 Keshava Biosciences LLC的总体目标是开发一种新的仿生肝脏模型， 微技术使生理和病理条件下的肝脏环境。凯沙瓦 Biosciences LLC与Kidambi博士（首席执行官兼生物工程师，具有仿生肝脏方面的专业知识）合作 模型）率先使用仿生“BEASTS（生物工程粘合剂硅氧烷基板， 可调刚度）”平台，该平台能够保存原代人肝细胞（PHH），包括肝- 特异性合成功能（尿素和白蛋白生成;胆汁酸摄取），维持ADH和CYP 2 E1 活动10天。BEASTS平台独特地再现了生理（2 kPa）和病理性肝脏硬度 在ALD的各个阶段（8、15、25、55 kPa），以允许模拟ALD患者中的纤维化， 目前的动物模型。该模型将在3个步骤中进行优化：优化机械损伤， 损伤表型的优化和阳性对照化合物的治疗效果的优化。 这些工具有望逐步取得临床成功，取代完全临床失败的现状。 最终，这项颠覆性技术将能够快速筛选药理化合物， 对ALD的有益或有害影响以及药物遗传学相互作用的检测。这也符合 （一）开发和验证工具、模型和技术;（二）开发 用于治疗ALD的候选药物。