FIBULIN-5 & WALL STRESSES IN VASCULAR REMODELING: THEORY AND EX VIVO EXPERIMENTS

FIBULIN-5

• 批准号: 7254459
• 负责人: RUDOLPH L GLEASON
• 金额: $ 20.68万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-24 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7254459
• 关键词: Abdominal Aortic Aneurysm; Age; Aging; Aneurysm; Arteries; Arteriosclerosis; Atherosclerosis; Attention; Balloon Angioplasty; Behavior; Biological; Biomechanics; Blood Vessels; Cadherins; Cells; Clinical; Clinical Pathology; Collagen; Collagen Fiber; Computer Simulation; Condition; Data; Development; Devices; Elastic Fiber; Elastin; Environment; Enzymes; Equation; Equilibrium; Evolution; Excision; Explosion; Extracellular Matrix; Extracellular Matrix Proteins; F-Actin; Failure; Fiber; Glycosaminoglycans; Goals; Growth; Hypertension; Integrins; Intervention; Knock-out; Laser Scanning Microscopy; Lasers; Life; Mammary Arteries; Measurable; Measures; Mechanics; Mediating; Metric; Microscopy; Modeling; Molecular; Mus; Organ Culture Techniques; Outcome; Physiological; Play; Process; Production; Protein Binding; Proteins; Purpose; Rate; Regulation; Risk; Role; Ruptured Abdominal Aortic Aneurysm; Scanning; Smooth Muscle; Smooth Muscle Myocytes; Staining method; Stains; Stents; Stress; Stretching; Structural Protein; Testing; Thinking; Time; Tissues; Tropoelastin; Validation; Vascular Graft; Vascular Graft Occlusion; Vascular remodeling; Veins; Whole Organism; Work; crosslink; design; fibulin; functional loss; in vivo; infancy; innovation; insight; mathematical model; multi-photon; novel; predictive modeling; pressure; research study; response; shear stress; soft tissue; success; theories; tissue culture; two-photon

DESCRIPTION (provided by applicant): Vascular growth and remodeling (G&R) plays a key role in many physiological (e.g., normal vascular development and aging) and pathophysiological processes (e.g., hypertension, arteriosclerosis, and aneurysms), as well as the success (or failure) of many clinical interventions (e.g., vein grafts, synthetic vascular grafts, stents, and balloon angioplasty). Despite the explosion of information on soft tissue G&R, from molecular level to the tissue and whole organism level, attempts at integrating these data into a predictive model is still in its infancy. The goal of the current proposal is to develop and test an innovative theoretical- experimental paradigm for characterizing the time-course of vascular remodeling that integrates a novel organ culture device, two-photon laser scanning microscopy (LSM), biaxial biomechanical testing, and multi-scale mathematical modeling. Our central hypothesis is that volume fractions, fiber directions, and stress-free states of elastic fibers, collagen fibers, and smooth muscle cells can be quantified via two-photon LSM in parallel with biaxial biomechanical data on live mouse CCAs and these data can be incorporated into a constrained mixture model to describe and predict temporal changes in material behavior in both normal (adaptive) and maladaptive remodeling. Whereas much attention has been paid to the role of wall shear stress and circumferential (hoop) stress in vascular remodeling, the role of axial stress has been largely overlooked. Many clinical observations, however, highlight the importance of axial remodeling in the vasculature; marked tortuousity in AAAs, mammary artery by-pass grafts, and many vessels with hypertension and aging are a few but a few examples. Elastic fibers are thought to endow arteries with their in vivo axial stain and the loss of functional elastic fibers (which occurs aneurysms, hypertension, and aging) may be associated with impaired axial remodeling and development of tortuousity. Fibulin-5 is an ECM protein that binds tropoelastin and fibrillins with ava3, ava5, and a9a1 integrins(60) to bridge elastic fibers with cells. Thus, fibulin-5 is likely a key protein involved in regulation of elastic fibers and thus key in axial remodeling. The aims of this proposal are to measure and characterize the biomechanical behavior and microstructural organization of CCAs from wild-type and fib-5-/- mice and observe and quantify the biomechanical and microstructural remodeling of CCAs from wild-type and fib-5-/- mice exposed to (a) increased axial extension (b) increase transmural pressure, or (c) combined increase in axial extension and pressure in organ culture. Successful realization of these aims will establish an innovative approach for studying vascular remodeling under normal and pathophysiological conditions that can be used gain insights toward the development clinical pathologies and the design of appropriate clinical interventions. Vascular remodeling plays a key role in many physiological (e.g., normal vascular development and aging) and pathophysiological processes (e.g., hypertension, arteriosclerosis, and aneurysms), as well as the success (or failure) of many clinical interventions (e.g., vein grafts, synthetic vascular grafts, stents, and balloon angioplasty). The purpose of this work is to develop an innovative approach for studying vascular remodeling that combines multi-scale computational modeling with tissue culture and multi-photon microscopy that can be used gain insights toward the development clinical pathologies and the design of appropriate clinical interventions.

描述（由申请人提供）：血管生长和重塑（G＆R）在许多生理学（例如正常的血管发育和衰老）以及病理生理过程（例如高血压，动脉粥样硬化和动脉粥样硬化和动脉粥样硬化）以及许多临床干预（E.G.，vects frects gronty gronty frincts gross gross，vefte（或失败）中，都起着关键作用。和气球血管成形术）。尽管从分子水平到组织和整个生物水平的软组织G＆R的信息爆炸爆炸，但仍在尝试将这些数据整合到预测模型中的尝试仍处于起步阶段。当前建议的目的是开发和测试创新的理论实验范式，以表征整合新型器官培养设备，两光片激光扫描显微镜（LSM），双轴生物力学测试和多尺度数学建模的血管重塑的时间。我们的中心假设是，可以通过双轴生物力学数据与活小鼠CCAS上的双轴生物力学数据平行地定量弹性纤维，胶原纤维和平滑肌细胞的体积分数，纤维方向和平滑肌细胞的无应力状态，并且可以将这些数据纳入约束的混合模型中，以描述和预测在物质上的构图和正常行为（适用于型号）。尽管对壁剪应力和圆周（箍）应力在血管重塑中的作用引起了很多关注，但轴向应激的作用在很大程度上被忽略了。然而，许多临床观察表明，轴向重塑在脉管系统中的重要性。 AAA，乳腺动脉旁移植物以及许多具有高血压和衰老的血管的明显曲折性是几个例子。弹性纤维被认为会赋予其体内轴向染色，功能性弹性纤维的丧失（发生动脉瘤，高血压和衰老）可能与轴向重塑受损和曲折的发育受损有关。 Fibulin-5是一种ECM蛋白，将tropoelastin和Fibrillins与AVA3，AVA5和A9A1整合素（60）结合，以桥接带有细胞的弹性纤维。因此，斐杜蛋白5可能是涉及弹性纤维调节的关键蛋白，因此是轴向重塑的关键。该提案的目的是衡量和表征来自野生型和fib-5 - / - 小鼠CCA的生物力学行为和微观结构组织，并观察并量化并量化CCA的生物力学和微结构重塑，从野生型和FIB-5-/ - 均增加了（A）的轴向范围（a）增加轴向的轴向增加（a）的轴向（a）增加轴向的轴向增加（a）轴向增加轴向的轴向增加了轴向范围（a）的轴向增加（a）。器官培养中的压力。这些目标的成功实现将建立一种创新的方法，用于在正常和病理生理条件下研究血管重塑，这些方法可以使用，可以将其用于发育临床病理学和设计适当的临床干预措施的设计。血管重塑在许多生理学（例如正常的血管发育和衰老）以及病理生理过程（例如高血压，动脉粥样硬化和动脉瘤）以及许多临床干预措施（例如，静脉植入，静脉移植物血管，综合晶状体）和Stents，Stents，Stents，Stents，Stents，Stents，Stents，Stents，Stents，Stents，Stents，Stents，Stents，Stents，Stents，Stents，Steents，Stents，Stents，Steents，Stents，Steents，Steents，Steents，Steents，Steents，Steents，Steents，Steents，Steents，Steents，Steents，Steents，Steents，Steents，成功（或失败），起着关键作用。这项工作的目的是开发一种创新的方法来研究血管重塑，将多尺度计算建模与组织培养和多光子显微镜结合使用，该方法可以使用，可以将其用于开发临床病理和适当临床干预的设计。