Vascular Cell Phenotype on Physiologically-relevant Bioengineered Substrata

生理相关生物工程基质上的血管细胞表型

• 批准号: 7872972
• 负责人: JOYCE Y WONG
• 金额: $ 41.97万
• 依托单位: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-22 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7872972
• 关键词: American; Animals; Arterial Occlusive Diseases; Arteries; Atherosclerosis; Attention; Award; Behavior; Behavior Control; Biochemical; Biocompatible Materials; Biological; Biological Models; Biomechanics; Biomedical Engineering; Biomimetics; Blood Vessels; Cardiovascular Diseases; Cause of Death; Cell Adhesion Molecules; Cell Extracts; Cells; Chemicals; Clinical; Collagen Type I; Complex; Cues; Data; Deposition; Development; Disease; Engineering; Environment; Extracellular Matrix; Extracellular Matrix Proteins; Feedback; Focal Adhesions; Foundations; Gelatinase A; Generations; Goals; Homeostasis; Hydrogels; Hyperplasia; Injury; Intervention; Lead; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Measurement; Mechanics; Migration Assay; Modeling; Molecular; Morphology; Nature; Oryctolagus cuniculus; PTK2 gene; Pathway interactions; Pattern; Phenotype; Physiological; Platelet-Derived Growth Factor; Play; Production; Property; Proteins; Regulation; Research; Role; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Stimulus; Stress; System; Techniques; Testing; Therapeutic Intervention; Tissue Engineering; Tissues; Traction; Transplantation; Validation; Vascular remodeling; Veins; Venous; Western World; base; cell behavior; cell type; clinically relevant; collagenase; combat; design; in vivo; inhibitor/antagonist; migration; neutralizing antibody; novel; novel therapeutics; protein expression; public health relevance; response; restenosis; tissue culture

DESCRIPTION (provided by applicant): While there have been vast improvements in vascular intervention to combat vascular occlusive diseases, restenosis (occlusion of the vessel) following the intervention remains a major clinical problem. The long-term goal of this proposal is to elucidate key factors that control changes in VSMC behavior associated with vascular occlusive disease and to design novel engineered biomaterials that can probe and control this behavior. While there have been extensive studies examining the biochemical effects of changes in the ECM, comparatively little attention has been focused on the effects of the biomechanical properties of the ECM on VSMC phenotype. Our preliminary data show that both (i) VSMC signaling induced by platelet-derived growth factor (PDGF) and (ii) VSMC directional migration are modulated significantly by substrate stiffness. We further find that substrate stiffness influences ECM deposition (collagen type I and III) and the production and secretion of matrix metalloproteinases (MMP) -2 and -9 that are known to degrade the matrix. Based on these observations, our central hypothesis is that the local mechanical environment has an essential role in vascular homeostasis and broad modulatory effects on the structural composition of ECM. We further hypothesize that initial injury promotes a VSMC phenotypic switch that subsequently contributes via positive feedback to the development of vascular occlusive diseases. To test these hypotheses, we will use a multi-scale approach to explore the effect of biomechanical environment on the molecular level, on cells, tissues, and tissue-engineered biomimetic model systems. We will use VSMCs and also native vessels from normal and atherosclerotic animals (Watanabe Hereditable Hyperlipidemic rabbit) to achieve clinical relevance. Specific Aim 1: Investigate the interrelationship of mechanical properties such as compliance and ECM and develop physiologically-relevant bioengineered model substrata. Specific Aim 2: Determine the effects of mechanical environment on VSMC phenotypic modulation on bioengineered substrata mimicking physiological and pathological conditions of blood vessels. Specific Aim 3: Characterize the effects of mechanical environment and biochemical changes on vessel behavior by tissue culture under in vivo-like conditions. Validation of our bioengineered substrata results in tissue cultures will yield valuable data, establishing a mechanistic foundation for elucidating the role of biomechanics on ECM remodeling and VSMC phenotype. The successful completion of these aims will lead to new strategies to control VSMC phenotype related to vascular occlusive disease by targeting regulation of ECM biomechanical properties of the vessel wall. PUBLIC HEALTH RELEVANCE: This proposal seeks to understand the mechanisms that control the switching behavior of a major cell type in blood vessels that play a key role in the progression of atherosclerosis the leading cause of death in the Western world. Through researching these specific mechanisms, we have the potential to uncover novel therapeutic strategies to treat cardiovascular disease.

描述（由申请人提供）：虽然在对抗血管闭塞性疾病的血管介入方面已经取得了巨大的进步，但介入后的再狭窄（血管闭塞）仍然是一个主要的临床问题。该提案的长期目标是阐明控制与血管闭塞性疾病相关的 VSMC 行为变化的关键因素，并设计能够探测和控制这种行为的新型工程生物材料。虽然已经有大量研究检查 ECM 变化的生化影响，但相对较少的注意力集中在 ECM 的生物力学特性对 VSMC 表型的影响上。我们的初步数据表明，(i) 由血小板衍生生长因子 (PDGF) 诱导的 VSMC 信号传导和 (ii) VSMC 定向迁移均受到基质硬度的显着调节。我们进一步发现基质硬度影响 ECM 沉积（I 型和 III 型胶原）以及已知会降解基质的基质金属蛋白酶 (MMP) -2 和 -9 的产生和分泌。基于这些观察，我们的中心假设是局部机械环境在血管稳态中起着重要作用，并对 ECM 的结构组成具有广泛的调节作用。我们进一步假设初始损伤促进 VSMC 表型转换，随后通过正反馈促进血管闭塞性疾病的发展。为了检验这些假设，我们将采用多尺度方法探索生物力学环境对分子水平、细胞、组织和组织工程仿生模型系统的影响。我们将使用 VSMC 以及来自正常和动脉粥样硬化动物（渡边遗传性高脂血症兔）的天然血管来实现临床相关性。具体目标 1：研究机械性能（例如顺应性和 ECM）的相互关系，并开发生理相关的生物工程模型基质。具体目标 2：确定机械环境对模拟血管生理和病理条件的生物工程基质上 VSMC 表型调节的影响。具体目标 3：通过体内条件下的组织培养来表征机械环境和生化变化对血管行为的影响。在组织培养中验证我们的生物工程基质结果将产生有价值的数据，为阐明生物力学对 ECM 重塑和 VSMC 表型的作用奠定机制基础。这些目标的成功完成将带来新的策略，通过针对血管壁 ECM 生物力学特性的调节来控制与血管闭塞性疾病相关的 VSMC 表型。公共健康相关性：该提案旨在了解控制血管中主要细胞类型转换行为的机制，这些细胞类型在动脉粥样硬化（西方世界主要死亡原因）的进展中发挥着关键作用。通过研究这些特定机制，我们有可能发现治疗心血管疾病的新治疗策略。