Phenotypic Continuum Between Cardiac Growth and Protection

描述（由申请人提供）：参与细胞保护的蛋白质通常也调节细胞生长。在心脏中，转录因子、细胞内信号激酶和磷酸酶、膜受体/转运蛋白和其他应激激活酶都被证明参与心脏缺血保护和器官肥大的典型生长反应。然而，这一观察结果在单个蛋白质背景之外的相关性尚不清楚。我们假设心脏的生长和保护是由共享核心亚蛋白质组的差异调节引起的行为。在本R21中，我们将开发和采用新的方法来检验这一假设。我们最近做了一个诱人的观察，失去Tec家族的非受体酪氨酸激酶的一个成员会使心脏对心脏保护和肥厚产生抵抗。这些发现——虽然完全出乎意料——支持了前面提到的关于生长和保护的假设，并为研究这些心脏表型之间的关系提供了理想的工具。尽管先前在非心脏系统的研究有证据，但Tec家族在心脏中的作用是完全未知的。我们将结合动物模型、定量蛋白质组学和生物信息学/数学建模来研究这些新的观察结果。我们的方法将揭示产生表型的紧急行为，这对于单独的假设驱动的研究来说是无法检测到的，并且非常适合R21机制，因为它是基于新的生理和生化数据的，它是由创新技术驱动的，它试图为心脏信号传导提供概念上的进步。我们的目的是(1)研究线粒体和核亚蛋白质组在保护和肥大期间的变化，(2)确定Tec家族激酶在这些相同表型期间完整蛋白复合物形成的变化。本应用程序的目标是创建一个新的概念和实验框架，在系统水平上询问心脏生长和保护之间的联系。心脏病影响着全世界数百万人，是基础科学研究的一个关键焦点。我们发现了一种新的信号蛋白模型，它既能保护心肌细胞免受心肌梗死引起的细胞死亡，又能诱导心肌细胞肥厚生长。我们正在采用一种创新的方法来检查涉及心脏这两种状态的细胞内过程，并开发新的工具来检查心血管系统中的信号转导。

DESCRIPTION (provided by applicant): Proteins involved in cellular protection often also regulate cellular growth. In the heart, transcription factors, intracellular signaling kinases and phosphatases, membrane receptors/transporters and other stress- activated enzymes have all been shown to be involved in both cardiac protection against ischemia and the prototypical growth response of the organ, hypertrophy. However, the relevance of this observation beyond the context of individual proteins is unclear. We hypothesize that growth and protection of the heart are behaviors that arise from differential modulation of a shared core subproteome. In this R21, we will develop and employ new approaches to test this hypothesis. We recently made the tantalizing observation that loss of a member of the Tec family of non-receptor tyrosine kinases renders the heart resistant to both cardiac protection and hypertrophy. These findings-while completely unexpected- support the aforementioned hypothesis regarding growth and protection and provide an ideal tool to examine the relationship between these cardiac phenotypes. Despite evidence from previous studies in non-cardiac systems, the role of the Tec family in the heart is completely unknown. We will investigate these novel observations using a combination of animal models, quantitative proteomics and bioinformatics/mathematical modeling. Our approach will reveal emergent behaviors that engender phenotype which would be undetectable to solely hypothesis-driven research and is well-suited for the R21 mechanism because it is well-grounded in novel physiological and biochemical data, it is driven by innovative techniques, and it seeks to provide a conceptual advancement for cardiac signaling. Our aims are (1) to investigate the changes in mitochondrial and nuclear subproteomes during protection and hypertrophy and (2) to determine changes in intact protein complex formation by Tec family kinases during these same phenotypes. The goal of this application is to create a novel conceptual and experimental framework to interrogate the connection between cardiac growth and protection at a systems level. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE Heart disease affects millions of people worldwide and is a critical focus for basic science research. We have discovered a new model of signaling protein involved in both the protection against heart attack-induced cell death and the induction of hypertrophic growth. We are taking an innovative approach to examine intracellular processes involved in these two states of the heart and developing new tools to examine signal transduction in the cardiovascular system.