Harnessing Glycoproteomics and Glycomics to Understand Cardiac Biology and Disease

利用糖蛋白组学和糖组学来了解心脏生物学和疾病

• 批准号: 10337288
• 负责人: Rebekah L. Gundry
• 金额: $ 76.11万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10337288
• 关键词: Biology; Cardiac; Cardiac Myocytes; Cardiotoxicity; Cell Surface Proteins; Cell surface; Cells; Data; Development; Disease; Disease model; Future; Genetic; Heart; Heart failure; Human; Ligands; Mass Spectrum Analysis; Membrane; Membrane Glycoproteins; Methodology; Methods; Monitor; Outcome Study; Pathology; Patient Care; Patients; Pharmaceutical Preparations; Pluripotent Stem Cells; Polysaccharides; Proteome; Reagent; Reproducibility; Research; Signal Transduction; Specificity; Speed; System; Technology; Therapeutic; Tissues; base; bioinformatics tool; biomarker panel; cell type; clinical application; drug testing; experience; glycoproteomics; improved; innovation; molecular phenotype; next generation; novel marker; programs; receptor; remote sensing; stem cell biology; stem cells; technology development; translational study

ABSTRACT Our research program develops and applies innovative mass spectrometry technologies, bioinformatics tools, and methodologies to transform our understanding of cell surface proteins and glycans and answer outstanding questions in stem cell biology and cardiac pathology. Our analytical platforms promote the development of new reagents and strategies to improve the quality and homogeneity of stem cell-derived cardiomyocytes for research and clinical applications and the discovery of strategies to monitor and treat patients with advanced heart failure. Specifically, our approaches enable the identification, characterization, and quantification of cell surface glycoproteins and glycans from small numbers of human cells. To date, we have developed new markers for identifying cardiomyocytes with high specificity and selecting maturation stage-specific stem cell derived cardiomyocytes to enable reproducible assessment and isolation of functionally-defined cells. Applying our technologies to primary human heart tissue, we have begun to develop cell-type specific views of the cell surface proteome and glycome within normal and failing hearts. We have also developed innovative bioinformatics tools to inform our next level of technology development to enhance our capabilities and improve the speed and accuracy with which we analyze our mass spectrometry data. The proposed studies build on these experiences to: 1) develop the next generation technology that will provide unparalleled specificity regarding the molecular phenotypes presented at the cell surface, information that is not possible to obtain by any current method, 2) develop marker panels that enable the assessment and selection of chamber- and maturation-stage specific stem cell derived cardiomyocytes without genetic editing, 3) define the cell-type specific receptors, membrane- bound ligands and secreted factors present in the normal human heart and how they change in disease to provide new understanding of intercellular signaling and inform the development of remote sensing markers to benefit the care of patients with advanced heart failure. The impact from the proposed studies lies within future applications and mechanistic studies that will be possible based on the approaches and data that we generate. As our program evolves to pursue mechanistic and translational studies of the molecules revealed by our discovery efforts, we expect the outcomes of these studies will broadly impact the development of strategies to improve the quality of stem cell derivatives to promote their utility for drug testing, disease modeling, and therapeutic applications, inform the development of cell-type directed payload delivery systems and drugs that avoid cardiotoxic effects, and yield new strategies to assess and treat advanced heart failure.

抽象的 我们的研究计划开发并应用了创新的质谱技术，生物信息学工具， 以及改变我们对细胞表面蛋白和聚糖的理解并回答出色的方法论 干细胞生物学和心脏病理学中的问题。我们的分析平台促进了新的发展 提高干细胞衍生心肌细胞质量和同质性的试剂和策略用于研究 以及临床应用以及发现监测和治疗晚期心力衰竭患者的策略。 具体而言，我们的方法可以实现细胞表面的识别，表征和定量 来自少量人类细胞的糖蛋白和聚糖。迄今为止，我们为 鉴定具有高特异性的心肌细胞并选择成熟阶段特异性干细胞 心肌细胞能够对功能定义的细胞进行可重复的评估和分离。应用我们的 原发性人心组织的技术，我们已经开始发展细胞类型的细胞表面视图 蛋白质组和糖果在正常和失败的心脏内。我们还开发了创新的生物信息学工具 告知我们下一个技术开发水平，以提高我们的能力并提高速度和 我们分析质谱数据的精度。拟议的研究以这些经验为基础 至：1）开发下一代技术，该技术将提供有关分子的无与伦比的特异性 在细胞表面呈现的表型，无法通过任何当前方法获得的信息，2） 开发标记面板，以评估和选择腔室和成熟阶段 干细胞得出的心肌细胞无基因编辑，3）定义细胞类型的受体，膜 - 正常人心脏中存在的结合配体和分泌因素，以及它们如何改变疾病为 提供对细胞间信号的新理解，并告知遥感标记的开发 受益于心力衰竭患者的护理。拟议研究的影响在于未来 基于我们生成的方法和数据，应用和机械研究将是可能的。 随着我们的计划的发展，以追求我们所揭示的分子的机械和翻译研究 发现工作，我们预计这些研究的结果将广泛影响战略的发展 提高干细胞衍生物的质量，以促进其用于药物测试，疾病建模和 治疗应用，告知细胞类型的有效载荷输送系统和药物的开发 避免心脏毒性作用，并产生新的策略来评估和治疗晚期心力衰竭。