BIOLOGY OF TISSUE ENGINEERED ENDOTHELIAL IMPLANTS

该资助一方面利用组织工程来检查内皮细胞生理学，另一方面检查心血管疾病的基础。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始于内皮防御机制的破坏，并通过破坏内皮防御机制而传播。然而，尚不清楚内皮控制是源于内皮在管腔边界的物理存在，还是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、设计新疗法和治疗所有血管疾病。该提案旨在更好地了解内皮细胞在调节血管增殖性疾病中的生化作用，超越内皮细胞在管腔界面建立的物理屏障力所建立的作用。我们在组织工程内皮细胞植入物方面的工作有助于增进对这一领域的理解。内皮细胞嵌入海绵状聚合材料中，其三维结构确保大量细胞可以放置在邻近目标组织的保护性支架中。 我们已经表征了嵌入细胞的细胞分泌活性，并证明了它们在聚合物装置内保留了内皮生长特征、免疫特性和活力。当植入受伤动脉周围时，预期的增殖性病变会显着减少。这些移植物使我们能够将结构与功能分开，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. 确定高等动物模型中血管对深度损伤的反应的哪个阶段是由内皮细胞移植物调节的。 2.阐明移植内皮细胞控制体内血管修复的生化合成功能。这个计划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。我们希望所学到的经验教训将在疾病血管病理生理学的基础细胞和分子生物学的最广泛背景下得到利用，并用于持续创造和应用心血管疾病的创新分子、细胞和药理学疗法。

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.