CAREER: Vascularization in Cardiac Fibrosis Models

职业：心脏纤维化模型中的血管化

• 批准号: 2145723
• 负责人: Perla Ayala
• 金额: $ 54.31万
• 依托单位: California State University-Long Beach Foundation
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2145723&HistoricalAwards=false
• 关键词: CAREER; Vascularization; Cardiac; Fibrosis; Models

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.

该奖项全部或部分根据2021年美国救援计划法案（公法117-2）资助。心力衰竭（HF）由于其高患病率、死亡率、发病率和护理成本而一直是主要的医疗保健问题。人类心脏在受伤后的修复能力有限，失去的细胞被纤维化疤痕所取代。心脏纤维化条件下血管的有限形成显著促进疾病进展;受损心肌中的血管化仍然是心肌梗死修复的中心和未解决的问题。该CAREER提案的目标是使用组织工程方法开发精确的疾病模型，以研究受损心脏纤维化组织的血管修复，并将包容性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，培训部分将扩大科学和工程领域代表性不足的妇女和学生的参与，最终有助于美国科学和工程劳动力的多样化。调查人员长期以来-长期的研究目标是发展新的组织模型的策略，以模拟不同病理生理条件下的基质重塑和血管化事件例如，在一个实施例中，本研究旨在研究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，这个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。所提出的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）设计概括MI后重塑过程的明确定义的心脏纤维化模型，（2）确定/复制内皮细胞对心脏纤维化进展的相互影响和纤维化对血管形成的作用，以及（3）研究设计一种血管化的工程心脏纤维化模型，该模型可以帮助阐明增强心脏血管化的机制和修复。从这项研究中获得的结果将集中在两个重要方面，限制心脏再生的再生疗法的成功，纤维化组织重塑的进展和促进持续心脏血管化的最佳方法。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。 新的见解将促进先进的再生疗法的发展，可以在临床上实施。这个奖项反映了NSF的法定使命，并已被认为是值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。