Multi-Omics Approach to Identify Cardiokines in Human iPSC Models

识别人类 iPSC 模型中心肌因子的多组学方法

基本信息

批准号：
10450844
负责人：
Edward Lau
金额：
$ 23.99万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-20 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10450844
关键词：
Address Adopted Biological Assay Biological Process Cardiac Cardiac Myocytes Cardiomyopathies Cardiovascular system Catalogs Cell model Cells Communication Computational Technique Contracts Data Development Dilated Cardiomyopathy Disease Disease Pathway Endothelial Cells Extracellular Space Fibroblasts Foundations Gene Expression Genes Goals Health Heart Heart Diseases Heart failure Human In Vitro Ligands Light Maps Mass Spectrum Analysis Mediating Modeling Multiomic Data Muscle Cells Natriuretic Peptides Normal Cell Nucleic Acids Pattern Phase Physiological Play Process Proteins Proteomics Research Role Signal Transduction Work causal variant cell type experimental study extracellular induced pluripotent stem cell induced pluripotent stem cell derived cardiomyocytes interest multiple omics novel protein function receptor single cell sequencing single-cell RNA sequencing stem cell model

项目摘要

The human heart actively releases protein messengers into the extracellular space. Recent work suggests that these secreted proteins, termed cardiokines, can mediate cellular crosstalk that plays important roles in the development of cardiomyopathies and heart failure. Although several classical cardiokines such as the natriuretic peptides have been extensively characterized, there have been few efforts to systematically catalog the proteins secreted by human cardiac cells. Using proteomics and human induced pluripotent stem cell (hiPSC) models, we recently created a draft map of the human cardiac secretome through identifying and contrasting secreted molecules from hiPSC-derived cardiomyocytes, cardiac fibroblasts, and endothelial cells. The results revealed a surprisingly large number of candidate cardiokines released from each cell type including many secreted proteins with uncharacterized function in the cardiovascular system. Moreover, we found broad changes in the secretome patterns of cardiomyocytes carrying dilated cardiomyopathy causal variants over normal cells. Building on these findings, our aims in the R00 phase are now to (i): identify cardiomyocyte secreted proteins that function in fibroblast crosstalk and predict the biological processes they regulate; and (ii) prioritize disease-relevant cardiokines and validate their effects on recipient fibroblast gene expression. To achieve these aims, we will employ a combination of computational, single-cell sequencing, and proteomics strategies building on hiPSC models as our foundation. If successful, the proposed research has the potential to uncover a number of novel secreted proteins and their function in human cardiac cells, and shed light on the role of cellular communications in the development and progression of cardiomyopathies.

人类心脏主动将蛋白质信使释放到细胞外空间。最近的工作表明这些分泌的蛋白质（称为心肌因子）可以介导发挥重要作用的细胞串扰心肌病和心力衰竭的发展。尽管一些经典的心肌细胞因子，例如利尿钠肽已被广泛表征，但很少有人做出系统性的努力对人类心肌细胞分泌的蛋白质进行分类。利用蛋白质组学和人类诱导多能性干细胞（hiPSC）模型，我们最近通过以下方法创建了人类心脏分泌组的草图识别和对比 hiPSC 衍生的心肌细胞、心脏成纤维细胞、和内皮细胞。结果显示释放了大量候选心脏因子来自每种细胞类型，包括许多在心血管中具有未知功能的分泌蛋白系统。此外，我们发现携带扩张的心肌细胞的分泌组模式发生了广泛的变化。心肌病相对于正常细胞的因果变异。基于这些发现，我们在 R00 阶段的目标现在的任务是 (i)：识别在成纤维细胞串扰中起作用的心肌细胞分泌蛋白并预测它们调节的生物过程； (ii) 优先考虑与疾病相关的心肌因子并验证其效果对受体成纤维细胞基因表达的影响。为了实现这些目标，我们将采用以下组合：以 hiPSC 模型为基础的计算、单细胞测序和蛋白质组学策略作为我们的基础。如果成功，拟议的研究有可能发现一些新的分泌物蛋白质及其在人类心脏细胞中的功能，并阐明细胞通讯在心脏细胞中的作用心肌病的发生和进展。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Harmonizing Labeling and Analytical Strategies to Obtain Protein Turnover Rates in Intact Adult Animals.

协调标记和分析策略以获得完整成年动物的蛋白质周转率。

DOI：
发表时间：
2022-07
期刊：
影响因子：
0
作者：
Hammond, Dean E;Simpson, Deborah M;Franco, Catarina;Wright Muelas, Marina;Waters, John;Ludwig, R W;Prescott, Mark C;Hurst, Jane L;Beynon, Robert J;Lau, Edward
通讯作者：
Lau, Edward

Defining the Roles of Cardiokines in Human Aging and Age-Associated Diseases.

定义心因子在人类衰老和年龄相关疾病中的作用。