Regulation of Signal Transduction to Treat Heart Failure

描述（由申请人提供）：在过去十年中，关于通过信号转导级联激活或抑制细胞过程影响心肌生物学各个方面的分子的知识出现了爆炸性增长。然而，尽管信号传导被广泛接受为心肌调节的基本机制，但网络的某些基本要素仍然模糊不清。例如，一旦激活，是什么控制着特定信号通路的持续时间和强度？特定的信号级联是如何在网络参与者的不和谐声音中占据主导地位的，以及同时发生的串扰，甚至是积极反馈与消极反馈之间的竞争？答案，至少部分，可以找到一个“分子计时器”，尚未在心肌方面进行研究。这种信号转导的导体，命名为Pin1，是细胞增殖，存活，承诺和衰老的关键决定因素。此外，从已发表的关于非心脏细胞和组织的报告中收集到的Pin1的靶点揭示了影响心肌生物学几乎每个方面的心脏活性分子的真正“谁是谁”。通过音乐类比，Pin1并不选择歌曲，而是设置节拍和音调，以确定哪种信号将被增强。这一建议将描绘一个新的机制，控制信号的持续时间和强度在心肌。实现这一建议的既定目标将揭示一个以前未知的层的监管复杂性，整合已知的心肌信号级联，从而提供新的可能性，协调控制的分子信号，以增强抵抗病理损伤，并加强再生和修复。该提案的创新在于通过Pin1协调信号传导的概念，并通过改变单个节点调节器以多方面的方式重新编程细胞反应。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。具体目标将表明：1）心肌存活、增殖和肥大信号传导由Pin1协调，2）Pin1活性的丧失导致心肌过早老化和相关的血液动力学性能下降，3）Pin1表达决定心肌存活、对病理损伤的抵抗、肥大性重构、修复潜力，并拮抗老化的分子表型。这些研究的意义在于Pin1对被认为是心肌生物学基石的多个典型转导级联的广泛影响，这意味着该提案的发现将与大部分心肌和再生医学科学界相关。总的来说，这些研究将解锁心肌生物学的一个新方面，并挑战研究人员在描绘细胞信号转导的“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纳入其中。

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.