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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要酒精性肝病（ALD）是世界范围内发病和死亡的主要原因之一。针对 ALD 的预防或治疗方法仍然面临挑战，目前尚无有效的治疗方法。目前存在ALD，但对于减少饮酒或肝移植目前缺乏。临床相关的实验模型阻碍了确定 ALD 预后指标和潜力的任何努力开发一种表现出严重酒精中毒的动物模型一直是一个挑战。迫切需要仿生体外模型来诱导损伤，例如纤维化或肝硬化。肝纤维化机制研究及药物及药物高通量筛选减少肝脏脂肪积累和/或防止纤维化反应产生的组合虽然一些体外平台最近报道了更病理相关的脂肪变性的发展。肝脏模型，它们缺乏可能提高模型相关性的动态（机械）线索的方法论和原位生物分析能力，限制了它们与个性化药物筛选的结合。尽管其中一些平台显示出体外维持几个关键肝细胞分化功能，这些平台均未展示乙醇脱氢酶 (ADH) 和 CYP2E1 持续一段时间的表达/活动对于酒精代谢和研究至关重要 ALD 的这种限制尤其值得注意，因为这些元素对于 ALD 的发展至关重要。 Keshava Biosciences LLC 的总体目标是开发一种紧密模仿肝脏的新型仿生肝脏模型通过微技术实现生理和病理条件下的肝脏环境。 Biosciences LLC 与 Kidambi 博士（具有仿生肝脏专业知识的首席执行官和生物工程师）合作模型）率先使用仿生“BEASTS（生物工程粘合剂硅氧烷基材，可调谐刚度）”平台，能够保存原代人肝细胞（PHH），包括肝细胞特定的合成功能（尿素和白蛋白的产生；胆汁酸的摄取），维持 ADH 和 CYP2E1 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），以模拟 ALD 患者缺乏的纤维化目前的动物模型将分三步进行优化：优化机械损伤，损伤表型的优化和阳性对照化合物治疗效果的优化。这些工具有望带来渐进的临床成功，取代临床全面失败的现状。最终，这种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也符合这一点。符合 NIAAA 的利益 - (i) 工具、模型和技术的开发和验证；(ii) 开发；治疗 ALD 的候选药物。