Mass-Spectrometry-Based Functional Proteomic and Phosphoproteomic Technologies and Their Application for Analyzing Ex Vivo and In Vitro Models of Hypertrophic Cardiomyopathy.
Mass-Spectrometry-Based Functional Proteomic and Phosphoproteomic Technologies and Their Application for Analyzing Ex Vivo and In Vitro Models of Hypertrophic Cardiomyopathy.
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DOI：
10.3390/ijms222413644
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发表时间：
2021-12-20
影响因子：
5.6
通讯作者：
Emili A
中科院分区：
文献类型：
--
作者：
Moore J;Emili A
肥厚型心肌病（HCM）是一种常染色体显性遗传疾病，被认为主要由肌节蛋白突变引起。尽管进行了广泛的遗传分析，但对于收缩蛋白中的单个突变如何导致HCM中所见的细胞，表型和病理生物学级联的多样化，还没有全面的分子框架。分子谱分析和系统生物学方法是阐明、定量和解释包括心肌病在内的广泛样本类型的动态信号传导途径和差异大分子表达谱的有力工具。尖端方法结合了联合收割机高性能分析仪器（例如，质谱法）与计算方法（例如，生物信息学）来研究基于功能性连接的感兴趣蛋白质的相对丰度的生物化学途径的比较活性。心脏研究将从这一工具包应用于心脏组织模型中受益匪浅，这概括了发病机制的关键方面。在这篇综述中，我们评估了最先进的基于质谱的蛋白质组学和磷酸化蛋白质组学技术及其在HCM体外和离体模型中的应用，以全面绘制驱动疾病进展的大分子改变，强调其定义基本生物系统的组成部分，HCM发病机制的基本机制基础，并治疗受影响患者队列中随后出现的不同临床结果。
Hypertrophic cardiomyopathy (HCM) is an autosomal dominant disease thought to be principally caused by mutations in sarcomeric proteins. Despite extensive genetic analysis, there are no comprehensive molecular frameworks for how single mutations in contractile proteins result in the diverse assortment of cellular, phenotypic, and pathobiological cascades seen in HCM. Molecular profiling and system biology approaches are powerful tools for elucidating, quantifying, and interpreting dynamic signaling pathways and differential macromolecule expression profiles for a wide range of sample types, including cardiomyopathy. Cutting-edge approaches combine high-performance analytical instrumentation (e.g., mass spectrometry) with computational methods (e.g., bioinformatics) to study the comparative activity of biochemical pathways based on relative abundances of functionally linked proteins of interest. Cardiac research is poised to benefit enormously from the application of this toolkit to cardiac tissue models, which recapitulate key aspects of pathogenesis. In this review, we evaluate state-of-the-art mass-spectrometry-based proteomic and phosphoproteomic technologies and their application to in vitro and ex vivo models of HCM for global mapping of macromolecular alterations driving disease progression, emphasizing their potential for defining the components of basic biological systems, the fundamental mechanistic basis of HCM pathogenesis, and treating the ensuing varied clinical outcomes seen among affected patient cohorts.
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