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.

项目摘要酒精性肝病（ALD）是世界上发病率和死亡率的主要原因之一。重要的为了开发针对ALD的预防或治愈方法仍然存在挑战。没有有效的治疗方法目前存在ALD，但用于减少饮酒或肝移植。当前的稀少度临床相关的实验模型阻碍了识别ALD探针和潜力的任何努力有效的治疗选择。开发一种表现出严重酒精的动物模型的挑战诱导损伤，例如纤维化或肝硬化。迫切需要在体外模型中均需要允许研究肝纤维化机制和药物的高通量筛查减少肝脏脂肪积累和/或防止产生纤维化反应的组合脂肪变性。虽然一些体外平台最近报道了更多具有病理相关的发展肝模型，他们的方法缺乏可能改善模型相关性的动态（机械）提示以及原位生物分析能力，将它们可能与个性化药物筛查的整合在一起。还，尽管其中一些平台显示了几种关键肝细胞分化功能的维护，但这些平台都没有证明酒精脱氢酶（ADH）和CYP2E1 持续时期的表达/活性对于酒精代谢至关重要阿尔德。由于这些要素对于ALD的发展至关重要，因此这种限制尤其值得注意。 Keshava Biosciences LLC的总体目标是开发一种新型的仿生肝模型，以模仿该模型通过微技术实现生理和病理状况的肝环境。 Keshava Biosciences LLC与Kidambi博士（首席执行官兼生物工程师拥有仿生肝专业知识）合作模型）率先使用了仿生的“野兽（生物工程的粘合剂硅氧烷底物）可调节刚度）”平台，它可以保存原代人肝细胞（PHH）特定的合成功能（尿素和白蛋白产生；胆汁酸的吸收），维持ADH和CYP2E1 活动10天。野兽平台独特地重现生理学（2 kPa）和病理肝僵硬在ALD的各个阶段（8、15、25、55 kPa），以模仿ALD患者的纤维化当前的动物模型。该模型将通过3个步骤进行优化：机械感染的优化，损伤表型的优化和阳性对照化合物的治疗作用的优化。这些工具具有逐步临床成功的承诺，以代替总临床失败的现状。最终，这种破坏性技术将使药物化合物快速筛选对ALD和检测药物相互作用的有益或有害影响。这也是一致的与NIAAA的利益 - （i）工具，模型和技术的开发和验证；（ii）发展治疗ALD的候选药物。