Restoring Mycocardial Healing

描述(申请人提供)：心肌具有固有的细胞替代能力，但这种修复过程不足以应对急性损伤或慢性应激。在利用捐献的干细胞群体或表达旁分泌因子(或两者)来增强心肌修复方面取得了显著的进展，但过继转移的细胞生成新心肌的效果仍然不大。此外，一些研究表明，修复主要源于由细胞或分子治疗干预激活的内源性细胞的招募。这一计划的首要前提是内源性心肌修复机制受到病理刺激的影响，导致与细胞替代不足有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代和修复的分子信号。项目1(Sussman)研究了细胞外基质的作用。项目2(Heller Brown)专注于G蛋白偶联受体信号转导。项目3(Glembotski)涉及分泌/心动素合成，项目4(Gustafsson)描述了线粒体功能在再生过程中的作用。消除细胞替代的病理障碍将增加功能心肌的形成，改善血流动力学性能。同时加强治疗以促进愈合，然后可以受益于改善的内源性功能修复，导致更有效的心脏对病理应激的补偿。损害内源性替代细胞存活、增殖、迁移、承诺或整合到应激心肌的病理信号需要被定义、缓解和最佳逆转，以恢复心肌修复。该计划中的项目将展示造成修复能力丧失的分子机制，这些机制为心肌细胞的扩张或保留创造了不允许的条件。这个项目的目标将是描绘这些有害的信号机制，并确定如何克服它们来恢复内源性细胞修复过程，从而修复受损的心脏。

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.