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

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不清楚。在这项工作中，提出了一项新的精心设计的实验研究，该研究使用具有相关生物学和结构特征的心脏细胞（心肌细胞和心脏成纤维细胞）来揭示潜在的生物学机制。该项目的成功完成将使人们更好地了解导致心脏病的原因。这项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。心脏缺血，包括急性心肌梗死(MI, ？心脏病和慢性缺血性心脏病（chronic IHD）是高度进行性的生物疾病，最终可导致灾难性的心力衰竭和死亡。缺氧被认为是缺血诱导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反应，导致心肌收缩功能障碍和不良重构。虽然心脏的病理生理反应，特别是在心肌梗死期间，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，导致在生物学上低估缺血诱导的心脏损伤方面存在重大知识空白。该职业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分析的局限性，并具有优于动物模型的转化优势。这项为期五年的计划的目标是在芯片上开发一种类似天然的三维（3D）心肌组织模型，并模拟缺血引起的心脏病变情况，为损伤后潜在的复杂生物和病理生理事件提供基本框架。所得的见解有望为开发使能技术开辟新的途径，以阐明控制缺血性心脏病的分子和细胞机制。此外，拟议的研究有可能推进基于多模式药物的治疗，特别是心脏和其他复杂器官/组织的修复和再生。这项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，这个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.