CAREER: Vascularization in Cardiac Fibrosis Models

该奖项全部或部分由《2021年美国救援计划法案》（公法117-2）资助。心力衰竭（HF）一直是一个主要的医疗保健问题，因为它的高患病率、死亡率、发病率和护理成本。人类心脏损伤后的修复能力有限，失去的细胞会被纤维化疤痕所取代。在心脏纤维化条件下，血管的有限形成显著促进疾病进展；受损心肌的血管化仍然是心肌梗死修复的核心和未解决的问题。本CAREER提案的目标是利用组织工程方法开发精确的病变模型来研究受损心脏纤维化组织的血管修复，并将全纳教育和研究培训整合到研究工作的每个阶段。这一系统将有助于研究心脏病患者的有效治疗方法，培训部分将扩大女性和来自代表性不足背景的学生在科学和工程领域的参与，最终有助于使美国的科学和工程劳动力多样化。研究者的长期研究目标是推进策略，设计新的组织模型，模拟不同病理生理条件下的基质重塑和血管化事件，如心肌梗死后的纤维化进展，旨在深入了解组织修复机制，并最终建立新的治疗方法来控制心功能障碍和修复。为了实现这一目标，本CAREER项目的目的是增加对心脏纤维化条件下血管化机制的理解。提出的3D模型将模拟梗死纤维化心脏组织的重要特征。研究目标是：(1)设计明确的心脏纤维化模型，概括心肌梗死后的重塑过程；(2)确定/复制内皮细胞对心脏纤维化进展的相互影响以及纤维化在血管形成中的作用；(3)研究设计血管化的工程心脏纤维化模型，该模型具有血流，有助于阐明增强心脏血管形成和修复的机制。从这项研究中获得的结果将集中在两个重要方面，这两个方面限制了心脏再生再生治疗的成功，纤维化组织重塑的进展和促进持续心脏血管化的最佳途径。这些知识将有助于开发新的方法来调节病理性纤维化和内源性再生机制（包括血管生成）之间的平衡。新的见解将促进可在临床实施的先进再生疗法的发展。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

This award is funded in whole or in part under the American Rescue Plan Act of 2021 (Public Law 117-2). Heart failure (HF) persists as a major healthcare issue because of its high prevalence, mortality, morbidity, and cost of care. The human heart has limited capacity of repair after injury, and the lost cells are replaced by a fibrotic scar. The limited formation of blood vessels during cardiac fibrosis conditions significantly contributes to disease progression; vascularization in a damaged heart muscle is still a central and unresolved problem for cardiac muscle infarction repair. The objective of this CAREER proposal is to use a tissue engineering approach to develop precise diseased models to investigate vascular repair of damaged cardiac fibrotic tissue, and to integrate inclusive education and research training to every stage of the research work. This system will enable investigation of effective therapies for patients suffering with heart disease and the training component will broaden the participation of women and students from underrepresented backgrounds in science and engineering, eventually helping to diversify America's science and engineering workforce.The investigator's long-term research goal is to advance strategies to engineer novel tissue models that mimic matrix remodeling and vascularization events during different pathophysiological conditions e.g., fibrosis progression after myocardial infarction, aiming to gain insight on tissue repair mechanisms and to ultimately establish new therapeutic approaches to control cardiac dysfunction and repair. Towards this goal, the aim of this CAREER project is to increase understanding of the mechanisms of vascularization in cardiac fibrosis conditions. The proposed 3D models will mimic important characteristics of the infarcted fibrotic cardiac tissue. The research objectives are to: (1) Engineer well-defined cardiac fibrosis models that recapitulate the remodeling process post-MI, (2) Determine/replicate the reciprocal influence of endothelial cells on the progression of cardiac fibrosis and the role of fibrosis on vascularization, and (3) Investigate the design of a vascularized engineered cardiac fibrosis model with flow that could help elucidate mechanisms to enhance cardiac vascularization and repair. The results obtained from this study will focus on two important aspects that limit the success of regenerative therapies for cardiac regeneration, the progression of fibrotic tissue remodeling and the optimal approach to promote sustained cardiac vascularization. This knowledge will contribute to the development of novel approaches to modulate the balance between pathological fibrosis and endogenous mechanisms of regeneration, including angiogenesis. New insight will facilitate the development of advanced regenerative therapies that can be implemented in the clinic.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.