Vascular Growth and Regeneration

血管生长和再生

• 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
• 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

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集体知识已经从了解血管生成的努力中浮现出来， 内皮细胞从先前存在的血管中形成新的血管床的过程。 尽管如此，一旦形成，血管管也宽度，长度也膨胀，并且能够再生。 再生对于修复支架和其他造成的内皮损害极为重要 医疗设计，并在物理/化学创伤后介导治愈。但是我们对 在环境下调节内皮生长和再生的细胞和分子机制 在功能齐全的功能中，血液灌注和脉动血管受到限制。我们的初步数据表明 Tunica Intima在体内的膨胀是通过在A中的内膜内皮细胞的固有增殖而发生的 两极分化和有条理的方式。实际上，侧翼的内皮细胞的一部分是强烈诱导的 以高度同步的方式受伤后12小时进入细胞周期。这 过程是由触发分子重新布线和令人印象深刻的细胞细胞连接的变化引发的 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，新陈代谢的调整和快速出现 再生内皮特有的转录特征。这个新确定的签名是细腻的 通过定时释放压力信号的定时释放，这些信号似乎在内皮的子集中有差异化 细胞，揭示了一种内在的异质性，该异质性控制给定血管中再生的阈值。在 事实，使用内皮特异性彩虹小鼠使用的遗传追踪分析显示了细胞的存在 不同的增生潜力表明祖细胞在内皮壁中的插入 单层。综上所述，这些研究是用于理解机制的范式转移 控制内皮再生及其在诸如慢性/急性炎症之类的环境中， 衰老，慢性疾病和身体创伤。 通过此NHLBI杰出调查员奖的申请，我们的目标是（1）解码细胞和 控制形成血管内内皮膨胀过程的分子机制； （2）澄清 内皮再生和维修涉及的过程：（3）了解如何劫持这些 机制可能会加速或损害内皮再生； （4）确定新的目标 治疗性干预措施旨在在支架或其他伤害期间内皮修复。这些系列 广泛定义的目标已被概念化，以填补我们对基本生物学知识的空白 内皮细胞生物学中的过程，同时也利用此信息在医疗期间进行应用 干预措施，例如支架覆盖范围。这笔赠款提供的机会使我们充满活力 机制和这些研究的潜在翻译影响。