Engineering a cross-linked cellular network for cardiac repair

设计用于心脏修复的交联细胞网络

• 批准号: 10539723
• 负责人: Juliane Nguyen
• 金额: $ 48万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10539723
• 关键词: Address; Affinity; Area; Arrhythmia; Basic Science; Biodistribution; Bone Marrow; Cardiac; Cardiac Myocytes; Cell Therapy; Cell-Matrix Junction; Cells; Clinical Sciences; Clinical Trials; Data; Deposition; Disease; Dose; Drug Delivery Systems; Drug Kinetics; Engineering; Engraftment; Equilibrium; Evolution; Formulation; Genetic Engineering; Goals; Heart; Heart Diseases; Heart Injuries; Heterodimerization; In Situ; In Vitro; Individual; Infarction; Injectable; Injections; Integrins; Leucine Zippers; Link; Mediating; Mesenchymal Stem Cells; Modification; Myocardial Infarction; Myocardial Ischemia; Myocardium; Patients; Pharmaceutical Preparations; Protein Engineering; Proteins; Reaction; Reperfusion Therapy; Safety; Schedule; Site; Surface; System; Testing; Therapeutic; Treatment Efficacy; Vertebral column; base; cardiac repair; cell type; crosslink; density; design; exosome; heart function; immunogenic; improved; induced pluripotent stem cell; intravenous administration; mouse model; nanoparticle; novel; novel strategies; premature; prevent; receptor; regenerative; research and development; response; scaffold; stem cell function; therapeutic effectiveness

Project summary One bottleneck to achieving therapeutically relevant cell concentrations at the infarct site after myocardial infarction is the poor cell engraftment and retention of vehicles at the target site. Here we propose the first-of-its- kind, tunable, replenishable scaffold of cells that allows for multiple drug delivery "waves" to address this gap. We hypothesize that cardioregenerative cell accumulation and retention in the infarcted myocardium will be enhanced by surface decorating them with proteins that cross-link the cells via layer-by-layer assembly into a scaffold. Unlike conventional delivery strategies, which do not allow the subsequent accumulation of cells or carriers after saturation of the target infarct, each dose of cells in our platform will serve as a capturing surface for the next dose of cells. This will dramatically amplify the targetable surface area for additional waves of cell attachment and will also allow the total therapeutic concentration to be adjusted based on the number of doses administered. To prevent premature cross-linking, we will use engineered proteins that form heterodimers but not homodimers. These studies are expected to result in a new class of carrier-linked network that will not only substantially enhance cellular accumulation, retention, and local drug release at the infarct site to maximize therapeutic efficacy but also allow for several cycles of drug replenishment or personalized dosing in a non- invasive manner. Here, we aim to evaluate the safety and therapeutic effectiveness of this approach and assess the effect of surface modification on stem cell function. Successful completion of the proposed studies will transform the treatment of patients suffering from myocardial infarction.

项目摘要 心肌后，在梗塞部位实现治疗相关的细胞浓度的一种瓶颈 梗塞是在目标部位的细胞植入不良和车辆的保留。在这里，我们提出了首先 - 善良，可调节，可补充的细胞支架，允许多种药物输送“波”来解决这一差距。 我们假设心脏梗塞心肌中的心脏创收细胞积累和保留将是 通过表面用蛋白质进行表面装饰来增强它们，这些蛋白质通过逐层组件交联细胞中的蛋白质 脚手架。与常规交付策略不同，后者不允许随后的细胞积累或 目标梗塞饱和后的载体，我们平台中的每个细胞剂量都将用作捕获表面 对于下一个细胞。这将大大扩增可靶向的表面积，以增加细胞的额外波浪 附着，还将允许根据剂量数量调整总治疗浓度 管理。为了防止过早交联，我们将使用形成异二聚体但 不是同二聚体。预计这些研究将导致一类新的载体连接网络，不仅将 实质上增强了在梗塞部位的细胞积累，保留和局部药物释放，以最大化 治疗功效，但还允许在非 - 侵入性的方式。在这里，我们旨在评估这种方法的安全性和治疗效果并评估 表面修饰对干细胞功能的影响。成功完成拟议的研究将 改变患有心肌梗塞的患者的治疗。