Development and validation of a novel bioprinted, human-diabetic cardiac organoid model

新型生物打印人类糖尿病心脏类器官模型的开发和验证

基本信息

批准号：
10262910
负责人：
Binata Joddar
金额：
$ 30.2万
依托单位：
UNIVERSITY OF TEXAS EL PASO
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：
2020-09-15 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10262910
关键词：
3-Dimensional Address Adopted Affect Animal Experiments Animal Model Animals Biological Biosensor Blood Cardiac Cardiac Myocytes Cardiomyopathies Cardiovascular system Cell Differentiation process Cell Line Cell model Cell physiology Cells Clinical Clinical Trials Coculture Techniques Complex Complication Coupling Cues Custom Data Development Diabetes Mellitus Disease Disease Progression Drug Screening Economic Burden Electrophysiology (science)Endothelial Cells Environment Exhibits Exposure to Extracellular Matrix Fibrin Fibrinogen Fibroblasts Fostering Functional disorder Gap Junctions Gel Gelatin Glucose Goals Grant Growth Heart Heart Diseases Heart failure Human Human Cell Line Hyaluronic Acid Hyperglycemia In Vitro Individual Laboratories Left Ventricular Hypertrophy Memory Metabolic Methods Modeling Morphology Myocardial Infarction Myocardial tissue Myocardium Myopathy Non-Insulin-Dependent Diabetes Mellitus Nutrient Organoids Outcomes Research Oxygen Pathway interactions Patients Pattern Pharmaceutical Preparations Physiological Physiology Predisposition Primary Cell Cultures Printing Public Health Quality of life Risk Role Signal Pathway Source Stress Structural Protein Structure System Therapeutic Thrombin Time Tissue Model Tissues Toxicity Tests Translating Treatment Protocols Type 2 diabetic United States United States National Institutes of Health Validation base bioprinting blood glucose regulation cardiac tissue engineering chemical threat clinically significant design diabetic diabetic cardiomyopathy diabetic patient disease phenotype drug development genetic information heart preservation high risk human model human tissue in vivo induced pluripotent stem cell ischemic injury mixed cell culture mortality negative affect novel novel therapeutic intervention pre-clinical preservation prevent scaffold screening socioeconomics stem cell differentiation stem cell model targeted treatment

项目摘要

Cardiomyopathy is a debilitating complication of type-2 diabetes that predisposes patients towards increased risk of heart failure due to the disorder of the heart muscle that compromises its ability to circulate blood through the body and maintain a normal electrical rhythm, effectively. Despite its immense clinical impact, there is a lack of targeted treatment regimen for diabetic cardiomyopathy due to the intricate pathophysiology of the condition that makes drug screening problematic. Current therapeutic strategies developed on results originating from animal experiments, do not transform well to humans in vivo. Hence, studies should be based on laboratory engineered ‘cardiac tissue’ models biofabricated from human induced pluripotent stem cell (iPSC) differentiated cardiomyocytes that are essential to preserve in vivo physiology, and mimic disease progression. But, there is lack of such preclinical human tissue based models to establish a screening platform for the identification of potential therapeutics that will preserve cardiac cell physiology and function when exposed to diabetic stress. To address this need, we will develop a unique ‘cardiac organoid’ system that will be assembled using bioprinting of human cardiac cells, including cardiomyocytes (CM), fibroblasts (CF) and endothelial cells (EC), specifically sourced from diabetic donors. Bioprinting will enable the creation of an environment to nurture the development of physiologically relevant cues, resulting in a functional tissue construct with appropriate consistency. Cells derived from diabetic donors will retain their disease phenotype or `metabolic memory', which will be valuable to observe and study their structural and functional changes when exposed to hyperglycemic environments. Human iPSC sourced from type-2 diabetic donors will be custom differentiated into CM and mixed with CF and EC for bioprinting of ‘cardiac organoids’ that will be exposed to normal and hyperglycemic conditions to delineate between the effects caused by metabolic memory, hyperglycemia and a combination of both. Results will help in understanding the role of the signaling pathways involved in disease progression, which may guide and inform us towards designing an enhanced therapeutic approach for rescuing cardiac tissues from hyperglycemic insult. The successful completion of these studies will lead to establishment of a patient-specific iPSC model of human type-2- diabetes, and reveal the power of this approach for discovery of new therapeutic strategies for a complex metabolic condition with rising clinical significance.

心肌病是 2 型糖尿病的一种使人衰弱的并发症，使患者容易患上由于心肌紊乱而导致心力衰竭的风险增加它能够有效地消除体内血液并维持正常的电节律。尽管其临床影响巨大，但糖尿病缺乏针对性的治疗方案心肌病由于病情复杂的病理生理学而需要进行药物筛选目前的治疗策略是根据动物实验结果制定的。实验表明，在人体体内不能很好地转化，因此，研究应该基于。由人类诱导多能干细胞生物制造的实验室工程“心脏组织”模型细胞（iPSC）分化的心肌细胞对于保持体内生理学至关重要，以及但是，缺乏这种基于临床前人体组织的模型来模拟疾病进展。建立一个筛选平台来识别潜在的治疗方法，以保留暴露于糖尿病应激时心脏细胞的生理和功能为了满足这一需求，我们。将开发一种独特的“心脏类器官”系统，该系统将使用人体生物打印进行组装心肌细胞，包括心肌细胞（CM）、成纤维细胞（CF）和内皮细胞（EC），专门来自糖尿病捐赠者的生物打印将能够创造一个环境。培育生理相关线索的发展，形成功能组织具有适当一致性的构建体来自糖尿病供体的细胞将保留其疾病。表型或“代谢记忆”，这对于观察和研究其结构和暴露于高血糖环境时的功能变化。 2 型糖尿病供体将被定制分化为 CM 并与 CF 和 EC 混合以用于 “心脏类器官”的生物打印将暴露在正常和高血糖条件下描述代谢记忆、高血糖和以下因素的组合所造成的影响两者的结果都将有助于理解信号通路在疾病中的作用。进展，这可以指导和告知我们设计一种增强的治疗方法成功完成了从高血糖损伤中拯救心脏组织的方法。这些研究将导致建立人类 2 型患者特异性 iPSC 模型糖尿病，并揭示了这种方法对于发现糖尿病新治疗策略的力量复杂的代谢状况具有越来越高的临床意义。