CAREER: Cardiac Ischemia On-a-Chip: Probing Mechanisms Underlying Molecular, Cellular and Tissue-Level Adaptive Responses After Injury

主要研究者：Nikkhah，Mehdi提案编号：1653193心脏病发作（心肌梗死）是导致死亡的主要原因，但其潜在的生物学机制尚未完全了解。在这项工作中，提出了一种新的精心设计的实验研究与心脏细胞（心肌细胞和心脏成纤维细胞）与相关的生物学和结构特征，以揭示潜在的生物学机制。该项目的成功完成将导致对心脏病原因的更好理解。该职业计划的教育和推广旨在使高中教师受益，并激发K-12学生对科学、技术、工程和数学（STEM）的长期兴趣。心脏病发作？）和慢性缺血性心脏病（慢性IHD）是高度进行性的生物学疾病，其可最终导致灾难性心力衰竭和死亡。缺氧被认为是缺血性心脏损伤的主要调节因子，通过触发大量分子和细胞信号级联，导致心肌收缩功能障碍和不良重塑。虽然心脏的病理生理学反应，特别是在MI期间，一直是使用金标准动物模型进行深入研究的主题，但缺乏对微环境线索的精确控制以及无法完全概括人体生理学，导致在缺血诱导的心脏损伤的生物学理解方面存在重大知识缺口。该CAREER计划旨在满足开发替代平台技术的关键需求，该技术解决了当前体外试验的局限性，并具有优于动物模型的转化优势。这个为期五年的项目的目标是在芯片上开发一个类似天然的三维（3D）心肌组织模型，并模拟缺血诱导的心脏疾病，为损伤后潜在的复杂生物学和病理生理学事件提供一个基本框架。 这些见解有望为开发能够阐明缺血性心脏病的分子和细胞机制的技术开辟新的途径。此外，拟议的研究有可能推进基于多模式药理学的治疗，特别是心脏的修复和再生，以及其他复杂的器官/组织。该职业计划的教育和推广旨在使高中教师受益，并激发K-12学生对科学，技术，工程和数学（STEM）的长期兴趣。拟议的举措还将为STEM领域的下一代本科生和研究生提供跨学科培训。此外，该职业计划将带来生物工程科学家和心血管医学临床医生之间的协同增效作用。

PI: Nikkhah, MehdiProposal No: 1653193Heart attack (Myocardial infarction) is a leading cause of death, but its underlying biological mechanisms are not well understood. In this work, a novel well-designed experimental study is proposed with cells from the heart (cardiomyocytes and cardiac fibroblasts) with the associated biological and structural features for uncovering the underlying biological mechanisms. Successful completion of the project will result in an improved understanding of what causes heart diseases. The educational and outreach of this CAREER program have been designed to benefit high school teachers and stimulate long-term interest in K-12 students towards science, technology, engineering and mathematics (STEM).Cardiac ischemia, including acute myocardial infarction (MI, ?heart attack?) and chronic ischemic heart disease (chronic IHD), are highly progressive biological disorders that can ultimately lead to catastrophic heart failure and death. Hypoxia has been implicated as the major regulator of ischemia-induced cardiac injury, through triggering of a multitude of molecular and cellular signaling cascades, leading to contractile dysfunction and adverse remodeling of the myocardium. While the pathophysiological responses of the heart, specifically during MI, have been the subject of intensive studies using gold standard animal models, the lack of precise control over the microenvironmental cues and the inability to fully recapitulate human physiology have led to a major knowledge gap in biological understating of ischemia-induced cardiac injury. This CAREER program aims to meet the critical need for the development of an alternative platform technology that addresses the limitations of current in vitro assays and has translational advantages over animal models. The goal of this five-year program is to develop a native-like three dimensional (3D) myocardial tissue model on-a-chip and mimic ischemia induced cardiac diseased conditions to provide a fundamental framework on the underlying complex biological and pathophysiological events following injury. Insights derived are expected to open new avenues for the development of enabling technologies to elucidate molecular and cellular mechanisms governing ischemic heart disease. Additionally, the proposed study has the potential to advance multimodal pharmacological based therapies for repair and regeneration of the heart in particular, and other complex organs/tissues, in general. The educational and outreach of this CAREER program have been designed to benefit high school teachers and stimulate long-term interest in K-12 students towards science, technology, engineering and mathematics (STEM). The proposed initiatives will also provide interdisciplinary training for the next generation of undergraduate and graduate students in STEM fields. Furthermore, this CAREER program will bring collaborative synergy among bioengineering scientists and clinicians in cardiovascular medicine.