Optically Promoting Cardiac Maturation Using Engineered Peptides

使用工程肽光学促进心脏成熟

基本信息

批准号：
10683790
负责人：
Herdeline Ann Mallari Ardoña
金额：
$ 49.49万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-12 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10683790
关键词：
Action Potentials Address Adult Animal Model Architecture Automobile Driving Behavior Binding Biological Biophysics Calcium Cardiac Cardiac Myocytes Cardiovascular Diseases Cardiovascular system Cell Culture Techniques Cell Survival Cells Charge Chemical Stimulation Cues Drug Screening Electric Stimulation Electrodes Engineering Ensure Epitopes Film Frequencies Functional disorder Gene Expression Generations Goals Heart Diseases Heart Injuries Heating Human In Vitro Investigation Light Measurement Measures Mechanical Stimulation Mechanics Mediating Metabolism Methods Microelectrodes Modeling Monitor Muscle Cells Myocardium Nanostructures Neonatal Optics Peptide Library Peptides Phenotype Physiologic pulse Polymers Process Protocols documentation Rattus Reporting Research Resolution Risk Assessment Signal Transduction Site Source Stimulus Stress Structure Surface Technology Testing Therapeutic Tissues Toxicology Transducers Transfection Ventricular base biomaterial interface cardiac pacing cardiac regeneration cardiac tissue engineering chromophore conditioning design disease mechanisms study drug discovery electric field extracellular genetically modified cells high throughput screening human stem cells improved indexing induced pluripotent stem cell infection risk innovation instrumentation irradiation minimally invasive monomer nanoassembly non-genetic novel strategies optogenetics personalized medicine regenerative therapy response scale up spatiotemporal species difference stem stem cell based approach stem cells success temporal measurement wireless

项目摘要

PROJECT SUMMARY The promise of human stem cell-derived cardiomyocytes (hSC-CMs) opens doors towards the feasibility of personalized medicine against cardiac diseases and for performing more accurate drug discovery studies. Moreover, hSC-CMs overcome the issue of species differences when using animal models for high throughput screening studies. However, one of the bottlenecks for scaling up the use of hSC-CMs is their ability to accurately reflect the native structure and function of adult human cardiomyocytes. Current efforts to address this critical challenge involve maturation protocols that use biophysical cues such as electrical and mechanical stimulation. These methods often utilize electrode contacts for field stimulation, bulky instrumentation for mechanical or sustained chemical stimulation, or genetically modifying cells to be light-responsive. Although we have seen successes through these induction and stimulation approaches, the field would benefit from a stimulation approach with minimal culture contact to reduce risk of infection during long-term cultures, as well as a light-based approach with higher spatiotemporal resolution than electrode-based stimulation. Here, we propose a new paradigm for stimulating hSC-CMs towards maturation by interfacing these cells with peptide-based substrates that are engineered to convert light to electrical cues. Our team will develop peptides engineered with chromophore units and cell-binding epitopes as materials that can be used for photoelectrical conditioning of hSC-CMs towards maturation. The long-term goal of this project is to establish photoelectrical conditioning via engineered peptides as a viable method to electrically stimulate cardiomyocytes and promote hSC-CM maturation in an electrodeless and non-genetic manner, with higher spatiotemporal resolution than field stimulation. We hypothesize that transient charging and other associated light-induced processes at the cardiomyocyte-biomaterial interface can influence extracellular potential, resulting in the photoelectrical stimulation of hSC-CMs towards maturation. Our rationale for proposing a materials-based approach for stimulating hSC-CMs stems from previous reports of conjugated polymers being used as a photoactive substrate for triggering action potentials of other excitable cells. To test our hypothesis, we propose the following specific aims: (1) establishing design parameters for peptide nanoassemblies with optimal photostimulation efficiency; (2) test the cellular- and tissue-level impact of peptide-mediated photostimulation; and (3) elucidate the effect of the proposed photoelectrical conditioning method on hSC-CM maturation. By establishing the design rules for the proposed photoexcitable peptides for stimulating hSC-CMs and ensuring their capability to locally excite cardiac cells, this innovative approach offers a new strategy for a “wireless” stimulation of cardiac tissues and can significantly contribute towards addressing the grand challenge of stem cell immaturity. 1

项目摘要人类干细胞衍生的心肌细胞（HSC-CMS）的承诺为朝向针对心脏病的个性化药物的可行性和更准确的药物发现研究。此外，HSC-CMS在使用动物时克服了物种差异的问题高通量筛查研究的模型。但是，一种用于扩展使用的瓶颈 HSC-CMS是它们准确反映成人人的天然结构和功能的能力心肌细胞。当前应对这一关键挑战的努力涉及使用的成熟协议生物物理提示，例如电气和机械刺激。这些方法经常利用电子接触现场刺激的接触，机械或持续化学刺激的笨重仪器，或基因修饰细胞具有光响应性。尽管我们已经看到了这些成功诱导和刺激方法，该领域将受益于最小的刺激方法培养接触以减少长期培养过程中感染的风险以及一种基于光的方法与基于电极的模拟相比，时空分辨率更高。在这里，我们提出了一个新的通过将这些细胞与基于肽的细胞接口，刺激HSC-CM刺激HSC-CM的范式经过精心设计的底物将光转换为电气提示。我们的团队将开发肽由发色团单元和细胞结合表位设计为可用于的材料 HSC-CMS对成熟的光电条件。该项目的长期目标是通过工程辣椒作为一种可行的方法来建立光电调节心肌细胞并以无电和非遗传学方式促进HSC-CM成熟比场刺激更高时空分辨率。我们假设瞬态充电和其他相关的光诱导的心肌生物材料界面的过程会影响细胞外潜在的，导致HSC-CMS成熟的光电刺激。我们的理由提出一种基于物质的方法来刺激先前报告的HSC-CMS步骤共轭聚合物用作光活性底物，以触发其他动作电位令人兴奋的细胞。为了检验我们的假设，我们提出以下特定目的：（1）建立设计具有最佳光刺激效率的肽纳米仪的参数；（2）测试细胞和肽介导的光刺激的组织水平影响；（3）阐明提议的效果 HSC-CM成熟的光电调节方法。通过建立设计规则提议的光塑性辣椒用于刺激HSC-CMS并确保其本地令人兴奋的能力心脏细胞，这种创新的方法为心脏组织的“无线”模拟提供了一种新的策略并可以为解决干细胞不成熟的巨大挑战做出重大贡献。 1