GENES THAT CONTROL CELL NUMBER--GI/S CHECKPOINT

描述 (摘自申请人的摘要)从心肌梗塞中恢复的临床 心肌梗塞的部分原因是无法存活的脑室。 心肌细胞通过相应的， 细胞数量的补偿性增加。这突显了有限的容量 仅靠肥厚和有害影响恢复心脏质量 与肥大相关，进一步损害生存。正在进行的肌细胞 丢失似乎也可能是终末期心脏的最终贡献者 失败了。治疗心力衰竭的传统疗法旨在挽救 损害心肌，优化机械负荷，或增加 存活心肌细胞的机械性能。原则上，战略以 增加有功能的心室肌细胞的数量有可能 临床益处。(这一主题是由 NHLBI心力衰竭研究与现状特别强调小组 RFA。)三种互补的、基于基因的方法已经付诸实施。 关于这次合作中的心肌细胞数量问题 R01-转分化，细胞周期限制的操纵，以及 干扰细胞程序性死亡(细胞凋亡)的途径。病毒式传播 生心转录因子的递送与上游生心 罗伯特·施瓦茨博士将探索信号。迈克尔·施耐德博士和 Loren field将使用功能增益和丢失突变来剖析 体内的“有丝分裂后”表型，并将使用共沉淀或 相互作用克隆分离影响心肌内源性蛋白的研究 细胞周期退出。CDC25专家康斯坦丁·加拉克蒂奥夫博士将研究 G2/M转换的分子调节器，第二个检查点必须 对于要增加的单元格数量是无法克服的。机制与对策 将由Doug Mann博士进行测试，重点是 肿瘤坏死因子过表达引发扩张型心肌病 Alpha，以及人类心肌的研究。(摘要结束)

DESCRIPTION (Adapted from the applicant's abstract) Clinical recovery from myocardial infarction is thwarted, in part, by inability of surviving ventricular myocytes to reconstitute functional cardiac mass through a corresponding, compensatory increase in cell number. This highlights the limited capacity to restore cardiac mass by hypertrophy alone, and deleterious effects associated with hypertrophy that further impair survival. Ongoing myocyte loss also appears likely as an eventual contributor to end-stage heart failure. Conventional therapies for heart failure are aimed at rescuing jeopardized myocardium, optimizing mechanical load, or augmenting the mechanical performance of surviving myocytes. In principle, strategies to increase the number of functional ventricular myocytes have potential for a clinical benefit. (This theme is among the highest priorities expressed by the NHLBI Special Emphasis Panel on Heart Failure Research and the present RFA.) Three complementary, gene-based approaches have been brought to bear on the problem of cardiac cell number in this Collaborative R01-transdifferentiation, manipulation of cell cycle constraints, and interference with pathways for programmed cell death (apoptosis). Viral delivery of cardiogenic transcription factors and upstream cardiogenic signals will be explored by Dr. Robert Schwartz. Drs. Michael Schneider and Loren Field will use gain- and loss-of-function mutations to dissect the "postmitotic" phenotype in vivo, and will use co-precipitation or interaction cloning to isolate the endogenous cardiac proteins affecting cell cycle exit. Dr. Konstantin Galaktionov, an expert on Cdc25, will study molecular regulators of the G2/M transition, a second checkpoint that must be overcome for cell number to be increased. Mechanisms and countermeasures for cardiac apoptosis will be tested by Dr. Doug Mann, with emphasis on dilated cardiomyopathy triggered by overexpression of tumor necrosis factor alpha, and on investigations of human myocardium. (End of Abstract)