Regulation of CPC Function via Protein O-GlcN Acylation

心肌在梗死后不能有效地自我修复。最近的研究表明，常驻心脏祖细胞（CPCs）是一个尚未开发的治疗靶点。不幸的是，缺血后的心肌对心肌细胞的生存和潜在的心肌分化不利，因此限制了外源性心肌细胞在缺血后的有效修复。项目3将研究应激信号的生物学调控及其对CPC功能的影响。最近，一些报道表明心脏中独特的应激反应（0-GlcNAc）使分化的心肌细胞能够承受缺血后心肌的剧烈环境。蛋白0- glcn酰化发生在每一个被检查过的多细胞生物中；然而，这种应激信号在cpc中的作用尚不清楚。该项目将直接解决这一不足，以创造新的生物学见解。项目3将验证一个中心假设，即一个独特的报警信号（0-GlcNAc）在调节CPC功能中起着基本作用，它促进CPC存活，但可能通过维持CPC处于持续报警状态来限制真正的缺血后心肌发生。项目3将通过重点关注增殖（目标1）、生存（目标2）和分化（目标3），确定促适应应激信号0-GlcNAc对CPC功能的影响。本项目将使用一系列仔细控制的功能损失和功能获得方法。无论施舍的具体结果如何，由于所追求的问题的重要性，该项目将为心血管医学的一个令人兴奋的领域提供全新的见解。项目3将继续与项目1、2和4合作，了解O- glcnac酰化与NO-CO轴（项目1）、TNF-NFkB诱导炎症（项目2）和高血糖抑制CPC功能（项目4）之间的创新调控机制。蛋白0- glcn酰化在cpc中的作用是完全未知的。毫无疑问，该项目将通过采用创新的方法来理解CPC调节和病理生理学，从而建立新的生物学见解。

The myocardium is largely unable to effectively repair itself following an infarction. Recent work indicates that resident cardiac progenitor cells (CPCs) represent an under-developed therapeutic target. Unfortunately, the post-ischemic myocardium is an unfavorable environment for the survival and potential cardiomyogenic differentiation of CPCs, thereby limiting effective post-ischemic myocardial repair of exogenously administered CPCs. Project 3 will address the biological regulation of stress signaling and its impact on CPC function. Recently, several reports indicated a unique stress response (0-GlcNAc) in the heart that allows differentiated cardiac myocytes to withstand the violent environment of the post-ischemic myocardium. Protein 0-GlcNAcylafion occurs in every multicellular organism that has been examined; yet, nothing is known about the role of this stress signal in CPCs. This Project will directly address this deficiency to create new biological insights. Project 3 will test the central hypothesis that a unique alarm signal (0-GlcNAc) plays a fundamental role in regulating CPC function and that it promotes CPC survival, but may limit bona fide post-ischemic cardiomyogenesis by maintaining CPCs in a persistent state of alarm. Project 3 will establish the impact of the pro-adaptive stress signal, 0-GlcNAc, on CPC function by specifically focusing on proliferation (Aim 1), survival (Aim 2), and differentiation (Aim 3). This Project will use an exhaustive series of carefully controlled loss- and gain-of-function approaches. Regardless of the specific outcomes of the Alms, this Project will provide completely novel Insights into an exciting area of cardiovascular medicine because of the significance of the questions being pursued. Project 3 will continue to collaborate with Projects 1, 2, and 4 to understand innovative inter-regulatory mechanisms between O- GlcNAcylation and: the NO-CO axis (Project 1), TNF-NFkB induced inflammation (Project 2), and hyperglycemic suppression of CPC function (Project 4). The role of protein 0-GlcNAcylafion in CPCs is completely unknown. This Project will undoubtedly establish new biological insights by assuming an innovative approach to understanding CPC regulation and pathophysiology.