Nanoparticles and Arterial Disease

纳米颗粒与动脉疾病

基本信息

批准号：
7627301
负责人：
VIRGINIA M MILLER
金额：
$ 18.89万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-06-01 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7627301
关键词：
Address Affect Animals Antibodies Apoptosis Area Arterial Occlusive Diseases Arteries Arts Biochemical Biology Biosensor Blood Vessels Calcified Characteristics Chemicals Cholesterol Computers Cosmetics Data Department of Energy Development Diagnosis Disease Drug Delivery Systems Durapatite Engineering Equilibrium Etiology Exposure to Fixatives Future Goals Guidelines Health Histological Techniques Human Hyperplasia Image In Vitro Intravenous Investigation Kidney Calculi Knowledge Location Medical Medicine Molecular Nanotechnology Organ Oryctolagus cuniculus Osteoblasts Osteonectin Pathogenesis Pathogenicity Pathway interactions Plasma Prevention Prions Process Proteins Publishing Punch Biopsy Research Personnel Resolution Risk Sampling Site Smooth Muscle Myocytes Source Specimen Techniques Testing Tissues Toxic effect Vascular Diseases arterial lesion arterial remodeling base bone sialoprotein calcification catalyst cell injury computerized data processing design experience feeding high risk human disease human tissue implantable device improved in vivo matrix Gla protein microorganism multidisciplinary nanometer nanoparticle nanoscale nanoscience nanosized news novel osteopontin particle research study response sensor surface coating tomography

项目摘要

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.

描述（由申请人提供）：纳米技术正在蓬勃发展。纳米颗粒正在开发用于多种工业应用，例如数据处理和化妆品，以及用于靶向药物输送的医学、改善可植入设备和生物传感器的表面涂层。然而，有人担心接触这些纳米颗粒可能会造成健康风险。纳米尺寸的、自繁殖、自钙化颗粒已从患病的人体组织中分离出来，特别是肾结石和钙化动脉。尽管这些粒子的身份仍然存在争议，但它们的存在本身就提出了纳米粒子可能导致人类疾病的有趣可能性。例如，当将人钙化动脉匀浆繁殖的纳米颗粒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源纳米粒子可能致病的假设，但这种新颖且范式转变的概念将需要严格的科学证明。因此，R21 应用的目标是生成支持未来 R01 所需的初步/可行性数据，旨在测试人源纳米粒子具有致病性并加速动脉闭塞性疾病的中心假设。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取检验这一中心假设所需的初步数据。静脉注射人源纳米颗粒后，将对兔子动脉重塑的程度和质量进行量化。将比较纳米颗粒接种与胆固醇喂养和内皮剥脱相结合的效果。除了标准的组织学技术外，还将使用最先进的低温微型计算机断层扫描，其具有独特的优势，可以以高空间分辨率对高达 2 cm3 的组织样本进行成像，而无需通过切片和/或固定剂破坏它们。因此，可以对特定的钙化区域进行穿刺活检，以进行后续的生化分析和培养。这些实验具有很高的风险，因为尚不清楚人源纳米颗粒是否会导致动脉钙化。然而，需要了解这些人源纳米颗粒是否以及如何影响血管生物学，从而平衡风险。因此，这些实验填补了现有知识的重要空白，并具有产生巨大影响的潜力。如果纳米粒子是动脉钙化的原因，那么这种疾病的预防、诊断和治疗将发生革命性的变化。由于纳米粒子被用于工业和商业目的，因此有必要检查其潜在的毒性。人源纳米颗粒已从钙化的人体组织中分离出来，但尚不清楚纳米颗粒是否是疾病过程的积极贡献者。因此，这些实验填补了现有知识的重要空白，并具有产生巨大影响的潜力。如果人源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，实验可以代表测试用于医疗或工业目的的其他纳米粒子的潜在毒性/致病性的范例。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Key role of alkaline phosphatase in the development of human-derived nanoparticles in vitro.

碱性磷酸酶在体外开发人源纳米颗粒中的关键作用。

DOI：
发表时间：
2011-03
期刊：
影响因子：
9.7
作者：
Hunter, Larry W;Shiekh, Farooq A;Pisimisis, George T;Kim, Sung;Edeh, Samuel N;Miller, Virginia M;Lieske, John C
通讯作者：
Lieske, John C

Proteomic evaluation of biological nanoparticles isolated from human kidney stones and calcified arteries.

从人类肾结石和钙化动脉中分离的生物纳米颗粒的蛋白质组学评估。

DOI：
发表时间：
2010-10
期刊：
影响因子：
9.7
作者：
Shiekh, Farooq A;Charlesworth, Jon E;Kim, Sung;Hunter, Larry W;Jayachandran, Muthuvel;Miller, Virginia M;Lieske, John C
通讯作者：
Lieske, John C

Characterization of biofilm formed by human-derived nanoparticles.

人源纳米粒子形成的生物膜的表征。