GROWTH-SUPPRESSIVE MECHANISMS IN VASCULAR SMC

描述(改编自申请者摘要)：一些血管 疾病状态，包括动脉硬化、全身和肺 高血压，以及血管移植、重建和再狭窄 动脉内膜剥脱术的特点是不正常或不规范 中膜来源的平滑肌细胞(SMC)的复制 核扩散通常受到严格限制。在此应用程序中， 调查人员建议研究收购背后的机制 属于静止的表型，这是成人血管壁中的SMC的典型特征。 他们提供的初步数据表明，SMC形成了膜层 胎鼠腹主动脉中膜(第17天)表现出非常高的复制力 活体内复制率(&gt；95%)；该复制率在以下时间大幅下降至&lt；5% 胎儿第19天：从动脉干培养的胎儿SMC(胎儿天数 13-14)或主动脉(胎儿第17天)表现出可遗传的自分泌生长 并在无血清条件下自由复制。 相反，从晚期胚胎(胎儿第20天或第21天)培养的SMC 或来自新生儿的病毒依赖于血清进行体外复制。这个 数据表明，SMC经历了从自分泌到非分泌的表型转换 在胎儿发育后期的某个时间点自分泌生长。他们提议 确定自分泌生长丧失的分子基础 潜力。具体地说，他们计划：i)确定细胞的模式 在胎儿、新生和成年大鼠的主动脉中复制，II)培养 从胎龄增加的胎儿主动脉中提取SMC并测定 自分泌增长潜力丧失的确切时间点，III) 确定推动自分泌增长的增长因素(S) 培养的胎儿SMC，iv)测定基因表达的变化 这是自分泌增长潜力丧失的基础，以及v) 确定基因表达是否在体内也发生了类似的变化。他们的 最终目标是了解调节SMC生长的机制 在正常血管壁上的抑制，理解为 阐明特定的内源生长抑制机制可能 为最终开发有效的治疗方法提供了基础 涉及无规则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.