Vascular Growth and Regeneration

项目描述/摘要 我们对血管生长的许多集体知识都来自于对血管生成的理解， 内皮细胞脱离原有血管形成新血管床的过程。 尽管如此，一旦形成，脉管也会在宽度、长度上扩张，并且能够再生。 再生对于由支架和其他血管支架引起的内皮损伤的修复是极其重要的。 医疗器械，以及物理/化学创伤后的调解愈合。然而，我们对 调节内皮生长和再生的细胞和分子机制 一个功能齐全的，血液灌注和脉动血管是有限的。初步数据显示， 体内图尼卡的扩张通过内膜内皮细胞的内在增殖发生， 两极分化和有组织的方式。事实上，伤口两侧的内皮细胞亚群被强烈诱导， 以高度同步的方式在损伤后12小时内进入细胞周期。的 这一过程是由细胞间连接的变化引发的，这些变化触发了分子的重新连接， 生理变化这些反应的重要结果包括内皮细胞的改变， 极性，诱导染色质重塑，调节代谢和快速出现一个新的细胞周期。 这是再生内皮所特有的转录签名。这个新发现的特征 通过定时释放压力信号进行调节，这些信号似乎在内皮细胞亚群中起不同作用， 细胞，揭示了一种内在的异质性，控制着给定血管的再生阈值。在 事实上，使用内皮特异性彩虹小鼠进行的遗传追踪分析显示， 不同的增殖潜力表明祖细胞插入内皮细胞壁内， 单层总之，这些研究是理解机制的范式转变 在慢性/急性炎症等情况下控制内皮再生及其失调， 衰老、慢性病和身体创伤。 通过这个NHLBI杰出研究者奖申请，我们的目标是（1）解码细胞， 控制形成血管内内皮扩张过程的分子机制;（2）阐明 参与内皮再生和修复的过程：（3）了解如何劫持这些 机制可能加速或损害内皮再生;（4）确定新的靶点， 在支架植入术或其他损伤过程中，针对内皮修复的治疗干预。这些系列 广泛定义目标已经概念化，以填补我们在基础生物学知识方面的空白 在内皮细胞生物学的过程中，而且还利用这些信息在医疗过程中的应用， 例如支架覆盖。我们被这笔赠款所提供的机会所激励 机制和这些研究的潜在翻译影响。

PROJECT DESCRIPTION / SUMMARY Much of our collective knowledge on vascular growth has emerged from efforts to understand angiogenesis, a process by which endothelial cells depart from pre-existent vessels to form new vascular beds. Nonetheless, once formed, vascular tubes also expand in width, length, and are able to regenerate. Regeneration is extremely important to the repair of endothelial damage imposed by stents and other medical devises, as well as to mediate heal after physical/chemical trauma. However our understanding of the cellular and molecular mechanisms that regulate endothelial growth and regeneration within the context of a fully functional, blood perfused and pulsatile vessel are limited. Our preliminary data show that expansion of the tunica intima in vivo occurs through intrinsic proliferation of intimal endothelial cells in a polarized and organized manner. In fact, a subset of endothelial cells flanking a wound are robustly induced to enter into the cell cycle as quickly as 12 hours following injury in a highly synchronized fashion. The process is initiated by changes in cell-cell junctions that trigger molecular rewiring and impressive physiological changes. Important outcomes of these responses include alterations in endothelial cell polarity, induction of chromatin remodeling, adjustments in metabolism and a quick emergence of a transcriptional signature that is unique to regenerative endothelium. This newly identified signature is finely tuned by the timed release of stress signals that appear to act differentially in the subsets of endothelial cells, revealing an intrinsic heterogeneity that controls the threshold for regeneration in a given vessel. In fact, genetic tracing analysis using endothelial-specific rainbow mice revealed the presence of cells with different proliferative potential suggesting the intercalation of progenitors within the wall of the endothelial monolayer. Taken together, these studies are paradigm shifting for understanding the mechanisms controlling endothelial regeneration and their deregulations in settings like chronic/acute inflammation, aging, chronic diseases and physical trauma. Through this NHLBI Outstanding Investigator Award application our goals are to (1) decode the cellular and molecular mechanisms controlling the process of endothelial expansion within a formed vessel; (2) clarify the process involved in endothelial regeneration and repair: (3) understand how hijacking these mechanisms might either accelerate or impair endothelial regeneration; (4) identify novel targets for therapeutic interventions aimed at endothelial repair during stenting or other injuries. These series of broadly defined aims have been conceptualize to fill gaps of our knowledge on fundamental biological processes in endothelial cell biology but also to exploit this information for application during medical interventions such as stent coverage. We are energized by the opportunity afforded by this grant mechanism and for the potential translational impact of these studies.