Restoring Mycocardial Healing

描述（由申请人提供）：心肌具有细胞替代的固有能力，但这种修复过程不足以科普急性损伤或慢性应激。显著的进步是显而易见的，在使用捐赠的干细胞群体或旁分泌因子的表达（或两者），以增强心肌修复，但过继转移细胞产生新的心肌的功效仍然有限。此外，一些研究表明，修复主要源于细胞或分子治疗干预激活的内源性细胞的募集。该计划的首要前提是内源性心肌修复机制受到病理刺激的损害，导致与细胞替代不足相关的心功能不全的螺旋式下降。因此，心肌修复的功能恢复将不可避免地需要破译损害细胞替换和愈合的分子信号。项目1（Sussman）研究细胞外基质的作用。项目2（Heller Brown）专注于G蛋白偶联受体信号传导。项目3（Glembotski）关注分泌/心脏因子合成，项目4（Gustafsson）描绘线粒体功能在再生过程中的作用。减轻细胞替代的病理障碍将增加功能性心肌的形成并改善血流动力学性能。同时增强治疗，以加强愈合，然后可以受益于改善内源性功能修复，导致更有效的补偿心脏的病理压力。损伤存活、增殖、迁移、定型或内源性替代细胞整合到应激心肌中的病理信号需要被定义、减轻和最佳逆转，以恢复心肌修复。该计划的项目将展示负责修复能力丧失的分子机制，这些机制为心源性细胞的扩增或保留创造了非许可条件。该计划的目标将是描述这些有害的信号传导机制，并确定如何克服它们，以恢复内源性细胞修复过程，治愈受损的心脏。

DESCRIPTION (as provided by applicant): The myocardium possesses an inherent capacity for cellular replacement, yet this reparative process is inadequate to cope with acute injury or chronic stress. Remarkable advances are evident in the use of donated stem cell populations or expression of paracrine factors (or both) to enhance myocardial repair, but efficacy of adoptively transferred cells to generate new myocardium remains modest. Moreover, several studies indicate that repair stems predominantly from recruitment of endogenous cells activated by cellular or molecular therapeutic interventions. The overarching premise of this program is that endogenous myocardial reparative mechanisms become compromised by pathologic stimuli leading to a downward spiral of cardiac insufficiency linked to inadequate cellular replacement. Therefore, functional restoration of myocardial repair will inevitably require deciphering the molecular signaling that impairs cellular replacement and healing. Project 1 (Sussman) examines the role of extracellular matrix. Project 2 (Heller Brown) focuses upon G-protein coupled receptor signaling. Project 3 (Glembotski) is concerned with secretion / cardiokine synthesis, and Project 4 (Gustafsson) delineases the role of mitochondrial function in the regenerative process. Relieving pathologic impediments to cellular replacement will increase formation of functional myocardium and improve hemodynamic performance. Concurrent enhancement therapies to potentiate healing can then benefit from improved endogenous functional repair, leading to more effective compensation of the heart to pathologic stress. Pathological signals that impair survival, proliferation, migration, commitment, or integration of endogenous replacement cells into the stressed myocardium need to be defined, mitigated, and optimally reversed in order to restore myocardial repair. Projects in this program will demonstrate molecular mechanisms responsible for loss of reparative capacity that create nonpermissive conditions for expansion or retention of cardiogenic cells. The goal of this program will be to delineate these deleterious signaling mechanisms and determine how they can be overcome to restore endogenous cellular repair processes that heal the damaged heart.