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: 7672785
• 负责人: JOYCE Y WONG
• 金额: $ 2.4万
• 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/7672785
• 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; Classification; Clinical; Collagen Type I; Complex; Condition; 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; Localized; 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; Public Health; 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; design; in vivo; inhibitor/antagonist; migration; mouse Smc1l1 protein; mouse Smc1l2 protein; neutralizing antibody; novel; novel therapeutics; protein expression; 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）：虽然血管干预措施有了很大的改善，以打击血管闭塞性疾病，但在干预措施后恢复病（骨骼的闭塞病）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，并设计可以探测和控制这种行为的新型工程生物材料。尽管已经进行了广泛的研究来研究ECM变化的生化作用，但几乎没有关注ECM对ECM对VSMC表型的生物力学特性的影响。我们的初步数据表明，（i）VSMC信号传导由血小板衍生的生长因子（PDGF）和（ii）VSMC方向迁移都通过底物刚度显着调节。我们进一步发现，底物刚度会影响ECM沉积（I型和III型胶原蛋白）以及基质金属蛋白酶（MMP）-2和-9的生产和分泌，这些蛋白酶（MMP）-2和-9已知会降解基质。基于这些观察结果，我们的中心假设是局部机械环境在血管稳态中具有至关重要的作用，并且对ECM结构组成的广泛调节作用。我们进一步假设最初的损伤促进了VSMC表型转换，该转换随后通过积极的反馈来促进血管闭塞性疾病的发展。为了检验这些假设，我们将使用一种多尺度方法来探索生物力学环境对分子水平，细胞，组织和组织工程化的仿生模型系统的影响。我们将使用VSMC和来自正常和动脉粥样硬化动物（渡边可遗传性高脂兔）的天然血管来实现临床相关性。特定目的1：研究机械性能（例如合规性和ECM）的相互关系，并发展与生理相关的生物工程模型基础。具体目标2：确定机械环境对VSMC表型调节对模仿血管生理和病理状况的生物工程底层的影响。特定目的3：表征机械环境和生化变化对在类体内条件下组织培养的血管行为的影响。对我们的生物工程底层的验证会导致组织培养物产生有价值的数据，从而为阐明生物力学在ECM重塑和VSMC表型中的作用而建立机械基础。这些目标的成功完成将导致新的策略来控制与血管闭塞性疾病有关的VSMC表型，通过靶向容器壁的ECM生物力学特性。公共卫生相关性：该提案旨在了解控制血管中主要细胞类型的转换行为的机制，在动脉粥样硬化进展中起着关键作用是西方世界中死亡的主要原因。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型治疗策略。