Regulation of Signal Transduction to Treat Heart Failure

描述（由申请人提供）：在过去的十年中，关于分子的知识发生了爆炸性的增长，这些分子通过信号转导级联来激活或抑制细胞过程，影响心肌生物学的各个方面。然而，尽管信号作为心肌调节的基本机制被广泛接受，但网络的某些基本要素仍然模糊不清。例如，一旦激活，是什么控制特定信号通路的持续时间和强度？特定的信号级联如何在网络玩家的杂音和并发串音中获得主导地位，甚至是正反馈与负反馈之间的竞争？答案，至少在一定程度上，可以从一种“分子计时器”中找到，这种计时器还有待于在心肌环境中进行研究。这种信号转导的导体被称为Pin1，是细胞增殖、存活、承诺和衰老的关键决定因素。此外，从非心脏细胞和组织的已发表报告中收集到的Pin1靶标揭示了一个名副其实的“名人赛”的心脏活性分子，它几乎影响心肌生物学的各个方面。通过音乐类比，Pin1不会选择歌曲，而是设置节奏和音调，以确定哪些信号将被增强。这一建议将描述一个新的机制来控制信号的持续时间和强度在心肌。完成这一提议的既定目标将揭示一个以前未知的调控复杂性层，它整合了已知的心肌信号级联，从而为分子信号的协调控制提供了新的可能性，以增强对病理性损伤的抵抗力，并促进再生和修复。该建议的创新之处在于通过改变单个节点调节器以多方面的方式协调Pin1信号和重编程细胞反应的概念。短期目标是确定Pin1在心肌细胞、干细胞和完整心肌中作用的机制基础，并评估操纵Pin1活性以提高对损伤的抵抗力和增强修复过程的后果。具体目标将证明：1)心肌存活、增殖和肥厚信号是由Pin1调控的；2)Pin1活性的丧失导致心肌过早衰老和相关的血流动力学性能下降；3)Pin1表达决定心肌存活、对病理性损伤的抵抗、肥厚重塑、修复潜力，并拮抗衰老的分子表型。这些研究的意义在于Pin1对作为心肌生物学基石的多个典型转导级联的广泛影响，这意味着本提案的发现将与心肌和再生医学科学界的很大一部分相关。总的来说，这些研究将揭开心肌生物学的一个新方面，并挑战研究人员在描述细胞信号转导的“音乐”最终如何在分子水平上选择和播放的基本基础时，将时间、强度和持久性的影响结合起来。

DESCRIPTION (provided by applicant): Over the past decade an explosive growth of knowledge has occurred regarding molecules that impact upon every aspect of myocardial biology via signal transduction cascades to activate or repress cellular processes. However, certain basic essentials of networking remain obscure despite widespread acceptance of signaling as a fundamental mechanism for myocardial regulation. For example, what controls the duration and intensity of a particular signaling pathway once activated? How do specific signaling cascade(s) achieve dominance among the cacophony of networked players and concurrent cross-talk or even competition between positive versus negative feedback? The answer, at least in part, can be found with a "molecular timer" that has yet to be studied in the myocardial context. This conductor of signal transduction, named Pin1, is a pivotal determinant of cellular proliferation, survival, commitment, and aging. Moreover, targets of Pin1 gleaned from published reports upon non-cardiac cells and tissues reveal a veritable "who's who" of cardioactive molecules that influence virtually every aspect of myocardial biology. By musical analogy, Pin1 does not choose the song, but instead sets the beat and the tone that determines which signaling will be potentiated. This proposal will delineate a novel mechanism for control of signaling duration and intensity in the myocardium. Accomplishing the stated aims of this proposal will reveal a previously unknown layer of regulatory complexity that integrates known myocardial signaling cascades, thereby offering new possibilities for coordinate control of molecular signaling to enhance resistance to pathologic damage and to potentiate regeneration and repair. The innovation of this proposal rests with the concept of coordination of signaling by Pin1 and reprogramming cellular responses in a multifaceted fashion by altering a single nodal regulator. The short term goal is to determine the mechanistic basis of Pin1 action in cardiomyocytes, stem cells, and the intact myocardium and assess the consequences of manipulating Pin1 activity to improve resistance to damage and enhance reparative processes. Specific aims will demonstrate: 1) Myocardial survival, proliferative, and hypertrophic signaling are orchestrated by Pin1, 2) Loss of Pin1 activity leads to premature aging of the myocardium and associated decline in hemodynamic performance, and 3) Pin1 expression determines myocardial survival, resistance to pathological injury, hypertrophic remodeling, reparative potential, and antagonizes the molecular phenotype of aging. The significance of these studies is the widespread impact of Pin1 upon multiple canonical transduction cascades accepted as cornerstones of myocardial biology, meaning that the findings of this proposal will be relevant to a large proportion of the myocardial and regenerative medicine scientific community. Collectively, these studies will unlock a new facet of myocardial biology and challenge researchers to incorporate the influence of timing, intensity, and durability when delineating the fundamental basis of how the "music" of cellular signal transduction is ultimately chosen and played on the molecular level. PUBLIC HEALTH RELEVANCE: Heart disease remains a major cause of morbidity and mortality in the United States, with long term care and hospitalization of patients a significant burden on the national health care system. Despite advances over the last several decades we are still not truly capable of addressing the fundamental issue in heart failure: the progressive loss of contractile function and viable tissue. This proposal focuses upon a novel fundamental molecular mechanism involving regulation of the timing and intensity for protective and regenerative signals in the heart to maintain cardiac structure and function resulting in extended quality of life and decreased medical cost.