Nanoparticles and Arterial Disease

描述（申请人提供）：纳米技术正在蓬勃发展。纳米粒子正在被开发用于各种工业应用，如数据处理和化妆品，以及用于靶向药物输送的医学，用于改善可植入设备和生物传感器的表面涂层。然而，有人表示，接触这些纳米级颗粒可能会对健康构成威胁。纳米尺寸的、自我繁殖的、自钙化的颗粒已经从患病的人体组织中分离出来，特别是从肾结石和钙化的动脉中。尽管这些颗粒的身份仍然存在争议，但它们的存在提出了纳米颗粒可能导致人类疾病的有趣可能性。例如，将从人钙化动脉匀浆中繁殖的纳米颗粒静脉注射到兔子体内，四周后检测到含有纳米颗粒的钙化动脉病变。然而，尽管这一证据支持人体来源的纳米颗粒可能致病的假设，但这一新颖的、范式转变的概念将需要严格的科学证明。因此，本R21应用程序的目标是生成所需的初步/可行性数据，以支持未来的R01，旨在测试人体来源的纳米颗粒具有致病性并加速动脉闭塞性疾病的中心假设。一个由经验丰富的研究人员组成的多学科团队将使用体内和体外方法获得验证这一中心假设所需的初步数据。兔静脉注射人源性纳米颗粒后动脉重构的程度和质量将被量化。比较纳米颗粒接种联合喂胆固醇和内皮剥落的效果。除了标准的组织学技术外，还将使用最先进的低温微计算机断层扫描技术，该技术具有独特的优势，可以在高空间分辨率下成像高达2 cm3的组织标本，而不会通过切片和/或固定物破坏它们。因此，可以对特定钙化区域进行穿刺活检，以便进行后续的生化分析和培养。这些实验具有高风险，因为尚不清楚源自人类的纳米颗粒是否会导致动脉钙化。然而，需要知道这些源自人类的纳米颗粒是否以及如何影响血管生物学来平衡风险。因此，这些实验填补了现有知识的重要空白，具有高影响的潜力。如果纳米颗粒是导致动脉钙化的原因，那么这种疾病的预防、诊断和治疗将会发生革命性的变化。由于纳米颗粒被用于工业和商业目的，因此对其潜在毒性的研究势在必行。已从钙化的人体组织中分离出人类来源的纳米颗粒，但尚不清楚纳米颗粒是否在疾病过程中起积极作用。因此，这些实验填补了现有知识的重要空白，具有高影响的潜力。如果人造纳米颗粒加速动脉钙化的发展，那么这种疾病的预防、诊断和治疗将会发生革命性的变化。此外，实验可能是测试用于医疗或工业目的的其他纳米颗粒的潜在毒性/致病性的范例。

DESCRIPTION (provided by applicant): Nanotechnology is burgeoning. Nanoparticles are being developed for such diverse industrial applications as data processing and cosmetics, and in medicine for targeted drug delivery, surface coatings to improve implantable devices and biosensors. However, concerns have been expressed that exposure to these nanosized particles could pose a health risk. Nanometer sized, self-propagating, self-calcifying particles have been isolated from diseased human tissue, in particular, kidneys stones and calcified arteries. Although the identity of these particles remains controversial, their mere existence raises the intriguing possibility that nanoparticles can contribute to human disease. For example, when nanoparticles propagated from homogenates of human calcified arteries were injected intravenously into rabbits, calcified arterial lesions containing nanoparticles were detected four weeks later. Nevertheless, although this evidence supports the hypothesis that human-derived nanoparticles could be pathogenic, this novel and paradigm-shifting concept will require rigorous scientific proof. Therefore the goal of this R21 application is to generate preliminary/feasibility data needed to support a future R01 aimed at testing the central hypothesis that human-derived nanoparticles are pathogenic and accelerate arterial occlusive disease. A multidisciplinary team of experienced investigators will use in vivo and in vitro approaches to obtain preliminary data needed to test this central hypothesis. Extent and quality of arterial remodeling will be quantified in rabbits following intravenous inoculation with human-derived nanoparticles. Effects of nanoparticle inoculation in combination with cholesterol feeding and endothelial denudation will be compared. In addition to standard histological techniques, state-of-the-art, cryostatic microcomputed tomography will be used that offers the unique advantage of imaging up to 2 cm3 tissue specimens at high spatial resolution without destroying them by sectioning and/or with fixatives. Therefore, specific areas of calcification can be punch biopsied for subsequent biochemical analysis and culture. These experiments carry high risk, because it is not known whether or not human-derived nanoparticles cause arterial calcification. However, risk is balanced by the need to know if and how these human-derived nanoparticles affect vascular biology. Therefore, these experiments fill an important gap in existing knowledge and have the potential for HIGH IMPACT. If nanoparticles are causal to arterial calcification, the prevention, diagnosis and treatment of this disease will be revolutionized. Because nanoparticles are being used for industrial and commercial purposes, it is imperative to examine there potential toxicity. Human-derived nanoparticles have been isolated from calcified human tissue but is not known whether nanoparticles are active contributors to the disease process. Therefore, these experiments fill an important gap in existing knowledge and have the potential for HIGH IMPACT. If human-derived nanoparticles accelerate development of arterial calcification, then prevention, diagnosis and treatment of this disease will be revolutionized. In addition, experiments may represent a paradigm to test the potential toxicity/pathogenicity of other nanoparticles used for medical or industrial purposes.