Vascular Growth and Regeneration

血管生长和再生

基本信息

批准号：
10542405
负责人：
M. LUISA IRUELA-ARISPE
金额：
$ 96万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-02-07 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10542405
关键词：
Acceleration Acute Address Aging Award Biological Process Blood Vessels Cell Cycle Cell Polarity Cells Cellular biology Chemical Injury Chronic Chronic Disease Data Endothelial Cells Endothelium Gene Expression Profile Genetic Goals Grant Growth Heterogeneity Hour Human Impairment Inflammation Injury Intercellular Junctions Intervention Knowledge Length Mediating Medical Metabolism Molecular Mus National Heart, Lung, and Blood Institute Natural regeneration Outcome Pathway interactions Physiological Process Proliferating Research Personnel Series Signal Transduction Stents Stress Therapeutic Intervention Trauma Tube Tunica Intima Width angiogenesis blood perfusion cell regeneration chromatin remodeling effective therapy endothelial regeneration endothelial repair healing in vivo intercalation monolayer new therapeutic target prevent progenitor regenerative repaired response restenosis translational impact translational potential vascular bed wound

项目摘要

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.

项目描述/摘要我们关于血管生长的大部分集体知识都来自于对血管生成的理解，内皮细胞离开先前存在的血管形成新血管床的过程。尽管如此，一旦形成，血管的宽度和长度也会扩张，并且能够再生。再生对于支架和其他药物造成的内皮损伤的修复极其重要医疗设备，以及调解物理/化学创伤后的愈合。然而我们的理解调节内皮生长和再生的细胞和分子机制功能齐全、血液灌注和搏动的血管是有限的。我们的初步数据表明体内内膜的扩张是通过内膜内皮细胞的内在增殖而发生的两极分化和有组织的方式。事实上，伤口侧翼的内皮细胞子集被强烈诱导损伤后 12 小时内以高度同步的方式进入细胞周期。这该过程是由细胞与细胞连接的变化启动的，这些变化触发分子重新布线并令人印象深刻生理变化。这些反应的重要结果包括内皮细胞的改变极性、染色质重塑的诱导、新陈代谢的调整以及快速出现再生内皮细胞特有的转录特征。这个新识别的签名很好通过压力信号的定时释放进行调节，这些信号在内皮细胞亚群中表现出不同的作用细胞，揭示了控制给定血管再生阈值的内在异质性。在事实上，使用内皮特异性彩虹小鼠进行的基因追踪分析揭示了具有以下特征的细胞的存在：不同的增殖潜力表明祖细胞嵌入内皮细胞壁内单层。总的来说，这些研究是理解机制的范式转变在慢性/急性炎症等环境中控制内皮再生及其失调，衰老、慢性疾病和身体创伤。通过 NHLBI 杰出研究者奖申请，我们的目标是 (1) 解码细胞和控制已形成血管内皮扩张过程的分子机制； (2)澄清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) 确定新靶标旨在支架植入或其他损伤期间内皮修复的治疗干预措施。这一系列的广泛定义的目标已被概念化，以填补我们在基本生物学方面的知识空白内皮细胞生物学过程，而且还利用这些信息在医疗过程中应用支架覆盖等干预措施。这笔赠款提供的机会让我们充满活力机制以及这些研究的潜在转化影响。