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、用于改进植入性设备和生物传感器的表面涂层。然而，人们担心暴露在这些纳米颗粒中可能会对健康构成风险。已经从患病的人体组织，特别是肾结石和钙化的动脉组织中分离出纳米尺寸的、自我繁殖的、自钙化的颗粒。尽管这些颗粒的身份仍然存在争议，但它们的存在本身就提出了一个耐人寻味的可能性，即纳米颗粒可能会导致人类疾病。例如，当从人钙化动脉匀浆中繁殖的纳米颗粒被静脉注射到兔子体内时，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类衍生的纳米颗粒可能致病的假设，但这一新的和范式转变的概念将需要严格的科学证据。因此，这项R21应用的目标是生成支持未来R01所需的初步/可行性数据，该R01旨在测试人类来源的纳米颗粒是致病和加速动脉闭塞疾病的中心假设。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来获得检验这一中心假设所需的初步数据。在静脉接种人类衍生纳米颗粒后，动脉重塑的程度和质量将被量化。将纳米颗粒接种与胆固醇喂养和内皮剥离相结合的效果进行比较。除了标准的组织学技术外，还将使用最先进的冷冻静态显微计算机断层扫描技术，它具有独特的优势，可以在高空间分辨率下对多达2厘米米的组织样本进行成像，而不会通过切片和/或使用固定剂破坏它们。因此，可以对钙化的特定区域进行穿孔活检，以进行后续的生化分析和培养。这些实验具有很高的风险，因为尚不清楚人类衍生的纳米颗粒是否会导致动脉钙化。然而，需要知道这些人类衍生的纳米颗粒是否以及如何影响血管生物学，从而平衡了风险。因此，这些实验填补了现有知识的一个重要空白，并具有产生巨大影响的潜力。如果纳米颗粒导致动脉钙化，这种疾病的预防、诊断和治疗将发生革命性的变化。由于纳米粒子正被用于工业和商业目的，因此检测其潜在毒性势在必行。人类衍生的纳米颗粒已经从钙化的人体组织中分离出来，但尚不清楚纳米颗粒是否对疾病过程起到了积极作用。因此，这些实验填补了现有知识的一个重要空白，并具有产生巨大影响的潜力。如果人类衍生的纳米颗粒加速动脉钙化的发展，那么这种疾病的预防、诊断和治疗将发生革命性的变化。此外，实验可能代表了一种范例，以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。

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.