BIOLOGY OF TISSUE ENGINEERED ENDOTHELIAL IMPLANTS

该基金一方面利用组织工程研究内皮细胞生理学，另一方面研究心血管疾病的基础。这两者是相互关联的。完整的内皮调节血管生物学的各个方面，确保血管静止并调节血管修复。许多心血管疾病似乎开始并通过破坏内皮防御机制而传播。然而，目前尚不清楚内皮控制是否源于内腔边界处内皮的物理存在或源于完整内皮细胞分泌的化合物。 这个问题的答案可能决定我们如何理解，诊断，设计新的治疗方法和治疗血管疾病的全部范围。该提议旨在更好地理解内皮细胞在调节血管增生性疾病中的生化作用，其高于并超出由内皮在管腔界面处建立的物理屏障力所建立的生物化学作用。我们在组织工程内皮细胞移植方面的工作有助于增加对这一领域的理解。内皮细胞包埋在海绵状聚合物材料内，其三维构型确保大量细胞可以放置在邻近靶组织的保护性支架中。 我们已经表征了包埋细胞的细胞分泌活性，并且已经证明了它们在聚合物装置内的内皮生长特性、免疫特性和活力的保留。当植入损伤动脉周围时，预期的增殖性病变显著减少。这些移植物使我们能够将结构与功能分离，特别是能够通过一系列实验探索两组目标。这些目标包括：1.在高等动物模型中确定血管对深部损伤的反应的哪个阶段受内皮细胞移植物的调节。2.阐明了生物化学合成功能，这些功能是移植的内皮细胞控制体内血管修复的基础。这个项目是我们第一次有机会将许多不同的学科聚集在一起来解决这些问题。我们希望，所吸取的经验教训将在疾病的血管病理生理学的基本细胞和分子生物学的最广泛的背景下得到利用，并继续创造和应用创新的分子、细胞和药理学疗法治疗心血管疾病。

This grant utilizes tissue engineering to examine endothelial cell physiology on one hand and the basis of cardiovascular diseases on the other. The two are interrelated. The intact endothelium regulates all aspects of vascular biology, insures vascular quiescence and regulates vascular repair. Many cardiovascular diseases appear to begin with and propagate through disruption of the endothelial defense mechanisms. Yet, it is not clear whether endothelial control arises from the physical presence of the endothelium at the lumenal border or from the compounds intact endothelial cells secrete. The answer to this question may dictate how we understand, diagnose, design new therapies for and treat the full gamut of vascular disease. This proposal seeks to understand better the biochemical role of the endothelial cell in regulating vasoproliferative diseases, above and beyond that established by the physical barrier forces established by the endothelium at the luminal interface. Our work with tissue-engineered endothelial cell implants has helped to add to understanding in this area. Endothelial cells are embedded within sponge-like polymeric materials whose three dimensional configuration insures that large number of cells can be placed in a protective scaffolding adjacent to target tissues. We have characterized the cell secretory activity of embedded cells, and have demonstrated their retention of endothelial growth characteristics, immune identity and viability within the polymeric devices. When implanted around injured arteries the expected proliferative lesions are dramatically reduced. These grafts allow us to divorce structure from function and in particular will enable exploration of two groups of aims with a series of experiments. These aims include: 1. Determination of which of the phases of the vascular response to deep injury in higher species animal models are regulated by endothelial cell grafts. 2. elucidation of the biochemical synthetic functions that underlie engrafted endothelial cell control of vascular repair in vivo. This program is the first opportunity we will have to bring many diverse disciplines together to address these issues. We hope that the lessons learned will be utilized in the broadest context of fundamental cell and molecular biology of the vascular pathophysiology of disease, and for the continued creation and application of innovative molecular, cellular and pharmacological therapies for cardiovascular disease.