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.

项目总结 心肌梗死后梗死区达到治疗相关细胞浓度的一个瓶颈 脑梗塞是指细胞在靶部位的植入和滞留不良。在这里，我们提出了第一个ITS- 一种可调节、可补充的细胞支架，允许多次给药“波”来弥补这一缺口。 我们假设心肌梗死后心脏再生细胞的积聚和滞留 通过用蛋白质修饰它们的表面，这些蛋白质通过逐层组装将细胞交联成一个 脚手架。与传统的传递策略不同，传统传递策略不允许随后积累细胞或 载体在靶区梗塞饱和后，我们平台中的每一剂量细胞都将作为捕获面 用于下一剂量的细胞。这将极大地放大细胞额外波的目标表面积 附件，还将允许根据剂量的数量调整总治疗浓度 管理。为了防止过早的交联，我们将使用形成异二聚体的工程蛋白，但 不是同源二聚体。这些研究预计将产生一类新的运营商链接网络，不仅将 显著增强细胞在梗塞部位的蓄积、滞留和局部药物释放，以最大限度地 治疗效果，但也允许几个周期的药物补充或个性化剂量在非 侵犯性的方式。在这里，我们的目标是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 转变心肌梗死患者的治疗方式。