Regulation of CPC Function via Protein O-GlcN Acylation

心肌在梗塞后很大程度上不能有效地自我修复。最近的研究表明，常驻心脏祖细胞（CPC）代表了一个欠发达的治疗目标。不幸的是，缺血后心肌对于CPC的存活和潜在的心肌分化是不利的环境，从而限制了外源性施用的CPC的有效缺血后心肌修复。项目3将解决应激信号的生物调节及其对CPC功能的影响。最近，一些报道指出，心脏中的独特的应激反应（0-GlcNAc）允许分化的心肌细胞耐受缺血后心肌的剧烈环境。蛋白0-GlcNAcylafion发生在每一个多细胞生物体，已经检查;然而，没有什么是知道的作用，这种压力信号在CPC。该项目将直接解决这一缺陷，以创造新的生物学见解。项目3将测试中心假设，即独特的警报信号（0-GlcNAc）在调节CPC功能中起着重要作用，它促进CPC存活，但可能通过维持CPC处于持续的警报状态来限制真正的缺血后心肌发生。项目3将通过专门关注增殖（目标1）、存活（目标2）和分化（目标3）来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详尽的精心控制的功能丧失和功能获得方法。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，以了解O-GlcNAc酰化与NO-CO轴（项目1）、TNF-NFkB诱导的炎症（项目2）和CPC功能的高血糖抑制（项目4）之间的创新相互调节机制。蛋白质0-GlcNAcylafion在CPC中的作用是完全未知的。该项目无疑将通过采用创新方法来理解CPC调节和病理生理学来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.