GROWTH SUPPRESSIVE MECHANISMS IN VASCULAR SMC

描述（改编自申请人的摘要）： 疾病状态包括动脉硬化、全身和肺部 高血压和血管移植物再狭窄，重建， 动脉内膜切除术的特征在于 复制的图尼卡中膜衍生的平滑肌细胞（SMC），其 扩散通常受到严格限制。 在本申请中， 研究人员建议研究获得的潜在机制， 静止表型的典型SMC在成人血管壁。 他们提供的初步数据表明，形成图尼卡的SMC 胎鼠主动脉中膜（交配后第17天）表现出很高的复制性 体内复制率（>95%）;该复制率福尔斯通过 胎儿第19天。 从动脉干培养的胎儿SMC（胎龄 13-14）或主动脉（胎仔第17天）表现出可遗传的自分泌生长 特征，并在血清剥夺条件下自由复制。 相反，从晚期胚胎（胎龄20或21天）培养的SMC 或来自新生儿的依赖于血清进行体外复制。 的 数据表明SMC经历了从自分泌到非自分泌的表型转换， 自分泌生长在胎儿发育后期的某个时候。 他们提出 以确定自分泌生长丧失的分子基础 潜力 具体来说，他们计划：i）确定细胞的模式 在胎儿、新生儿和成年大鼠主动脉中复制，ii）培养 从发育年龄增加的胎儿子宫内膜中提取SMC，并确定其在子宫内膜中的表达。 自分泌生长潜力丧失的确切点，iii） 确定负责驱动自分泌生长的生长因子 在培养的胎儿SMC中，iv）确定基因表达的变化 这是自分泌生长潜力丧失的基础，以及v） 确定在体内是否发生类似的基因表达变化。他们的 最终目的是了解介导SMC生长的机制 抑制在正常血管壁，与理解， 特定内源性生长抑制机制的阐明可 为最终开发有效的治疗方法提供基础 涉及不受调节的血管疾病的治疗策略 SMC复制。

DESCRIPTION (Adapted from Applicant's Abstract):A number of vascular disease states including arteriosclerosis, systemic and pulmonary hypertension, and the restenosis of vascular grafts, reconstructions, and endarterectomies are characterized by the abnormal or unregulated replication of tunica media-derived smooth muscle cells (SMC), whose proliferation is normally tightly restricted. In this application the investigators propose to study the mechanisms underlying the acquisition of the quiescent phenotype which typifies SMC in the adult vascular wall. They present preliminary data which show that SMC forming the tunica media of the fetal rat aorta (Day 17p.c.) exhibit a very high replication rate in vivo (>95%); this replication rate falls dramatically to <5% by fetal Day 19. Fetal SMC cultured from the truncus arteriosus (fetal Days 13-14) or aorta (fetal Day 17) exhibited heritable autocrine growth characteristics and replicated freely under serum deprived conditions. In contrast, SMC cultured from later stage embryos (fetal Day 20 or 21) or from neonates were dependent on serum for replication in vitro. The data suggest that SMC undergo a phenotypic switch from autocrine to non- autocrine growth at some point in late fetal development. They propose to determine the molecular basis for the loss of autocrine growth potential. Specifically, they plan:i) to determine the pattern of cell replication in the fetal, neonatal, and adult rat aorta, ii) to culture SMC from fetal aortas of increasing developmental ages and determine the exact point at which autocrine growth potential is lost, iii) to determine the growth factor(s) responsible for driving autocrine growth in cultured fetal SMC, iv) to determine the changes in gene expression which underlie the loss of autocrine growth potential, and v) to determine if similar changes in gene expression occur in vivo. Their ultimate goal is to understand the mechanisms which mediate SMC growth suppression in the normal vessel wall, with the understanding that the elucidation of specific endogenous growth suppressing mechanisms may provide a basis for the eventual development of effective therapeutic strategies for the treatment of vascular diseases involving unregulated SMC replication.