Biomarkers of Heart Regeneration

心脏再生的生物标志物

基本信息

批准号：
8709869
负责人：
RAVI KARRA
金额：
$ 12.41万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-02 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8709869
关键词：
Adult Affect Affinity Chromatography Arrhythmia Autocrine Communication Biological Markers Biology Brain natriuretic peptide Cardiac Cardiac Myocytes Cardiovascular Diseases Cardiovascular system Cell Lineage Cells Cessation of life Clinical Research Complement Complex Development Doctor of Philosophy Dominant-Negative Mutation Endocardium Epicardium Epidemic Epidemiologic Studies Fishes Foundations Future Gene Expression Gene Expression Profiling Heart Heart failure Homeostasis Human Infarction Injury Lead Mammals Measures Mediating Mentors Mus Myocardial Myocardial Infarction Myocardium Natriuretic Peptides Natural History Natural regeneration Neonatal Organism Orthologous Gene Outcome Paracrine Communication Patients Physiology Plasma Predisposition Proteins Proteomics Research Institute Research Personnel Ribosomes Role Scientist Serum Signal Transduction Stress Surveys Technology Testing Training Transgenic Organisms Translating Translational Research Variant Work Zebrafish autocrine cardiac regeneration career cell injury cell type comparative design experience extracellular in vivo in vivo regeneration novel novel marker overexpression paracrine pre-clinical prevent public health relevance receptor regenerative repository research study response response to injury therapeutic target treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Because injury to the human heart results in irreversible loss of myocardium, insults such as infarction often lead to heart failure, susceptibility to arrhythmia, and death. In stark contrast, zebrafish are able to regenerate functional myocardium following injury by cardiomyocyte proliferation. Recently, a low grade of cardiomyocyte proliferation has been described in the adult mammalian heart. Therapies to augment cardiac regeneration following injury are attractive strategies to prevent human heart failure. However, the complement of factors that facilitate regeneration are unknown. Here, we propose the use of unbiased proteomic profiling and cell- type specific gene expression profiling to identify the extracellular factors that orchestrate zebrafish heart regeneration. Our preliminar work has identified brain natriuretic peptide (nppb) as a secreted factor that is spatiotemporally related to heart regeneration. We will generate novel transgenic fish to conditionally overexpress nppb and a dominant negative form of its receptor in specific cell lineages using Cre/Lox technology. These experiments will allow for the determination of autocrine and paracrine roles for nppb and serve as a template for future work to study the mechanism of action for other factors identified. Finally, we will assess conservation of these factors followin injury to the regenerative neonatal mouse heart and the poorly- regenerative adult mouse heart. Factors preferentially induced in regenerating neonatal mouse hearts compared to adult mouse hearts represent candidate biomarkers for heart regeneration. Markers of cardiac injury and regeneration that are conserved following cardiac injury in zebrafish and mice will then be measured in a repository of plasma obtained from patients following myocardial infarction. Marker levels will be tested for relation to human cardiovascular outcomes. The proposed experiments will identify factors that coordinate zebrafish heart regeneration and potential factors to therapeutically augment mammalian cardiomyocyte proliferation. In addition, our focus on secreted factors with regeneration will contribute to the development of a biomarker toolbox for future epidemiologic studies to understand the role of regeneration in human cardiovascular disease. Over the next several years, I hope to become an independent clinician-scientist focusing on heart regeneration. I ultimately hope to become an established investigator studying how variation in cardiac homeostasis affects the development of cardiovascular disease, specifically heart failure. The outlined experiments will provide a foundation for future mechanistic work to better understand the factors the facilitate regeneration and for a set biomarkers to understand how cardiac homeostasis affects cardiovascular outcomes following infarction. My work will be mentored by Dr. Kenneth Poss, PhD, a pioneer and leader in regenerative biology. We will collaborate with the Duke Clinical Research Institute, allowing for the ideal training experience for a translational research career.

描述（申请人提供）：由于人类心脏损伤会导致心肌不可逆转的损失，因此梗塞等损伤通常会导致心力衰竭、心律失常和死亡。与此形成鲜明对比的是，斑马鱼在心肌细胞增殖损伤后能够再生功能性心肌。最近，在成年哺乳动物心脏中发现了低水平的心肌细胞增殖。增强损伤后心脏再生的疗法是预防人类心力衰竭的有吸引力的策略。然而，促进再生的补充因素尚不清楚。在这里，我们建议使用无偏蛋白质组分析和细胞类型特异性基因表达分析来识别协调斑马鱼心脏再生的细胞外因子。我们的初步工作已确定脑钠肽（nppb）是一种与心脏再生时空相关的分泌因子。我们将使用 Cre/Lox 技术培育新型转基因鱼，以在特定细胞谱系中有条件地过表达 nppb 及其受体的显性失活形式。这些实验将允许确定 nppb 的自分泌和旁分泌作用，并作为未来研究其他已确定因素的作用机制的工作模板。最后，我们将评估再生新生小鼠心脏和再生不良成年小鼠心脏受伤后这些因子的保存情况。与成年小鼠心脏相比，新生小鼠心脏再生时优先诱导的因子代表了心脏再生的候选生物标志物。然后，将在从心肌梗塞后患者获得的血浆库中测量斑马鱼和小鼠心脏损伤后保守的心脏损伤和再生标记。将测试标志物水平与人类心血管结果的关系。拟议的实验将确定协调斑马鱼心脏再生的因素以及治疗性增强哺乳动物心肌细胞增殖的潜在因素。此外，我们对再生分泌因子的关注将有助于开发生物标志物工具箱，用于未来的流行病学研究，以了解再生在人类心血管疾病中的作用。在接下来的几年里，我希望成为一名专注于心脏再生的独立临床医生科学家。我最终希望成为一名成熟的研究者，研究心脏稳态的变化如何影响心血管疾病，特别是心力衰竭的发展。概述的实验将为未来的机械工作奠定基础，以更好地了解促进再生的因素，并为一组生物标志物提供基础，以了解心脏稳态如何影响梗塞后的心血管结局。我的工作将由再生生物学领域的先驱和领导者 Kenneth Poss 博士指导。我们将与杜克临床研究所合作，为转化研究职业提供理想的培训体验。