Nanoparticles and Arterial Disease

纳米颗粒与动脉疾病

• 批准号: 7387132
• 负责人: VIRGINIA M MILLER
• 金额: $ 22.67万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7387132
• 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; Purpose; Range; Research Personnel; Resolution; Risk; Sampling; Site; Smooth Muscle Myocytes; Source; Specimen; Standards of Weights and Measures; Techniques; Testing; Tissues; Toxic effect; Vascular Diseases; Week; arterial lesion; arterial remodeling; base; bone sialoprotein; calcification; catalyst; cell injury; computerized data processing; concept; design; experience; feeding; 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; size; surface coating; tomography

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。纳米粒子正在开发用于数据处理和化妆品等多种工业应用，以及用于靶向药物输送的医学，用于改善植入式设备和生物传感器的表面涂层。然而，人们担心接触这些纳米颗粒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动脉中分离出纳米尺寸的、自传播的、自钙化的颗粒。虽然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，当从人类钙化动脉的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。尽管如此，尽管这些证据支持人类来源的纳米颗粒可能是致病性的假设，但这种新颖和范式转变的概念将需要严格的科学证明。因此，该R21申请的目标是生成支持未来R 01所需的初步/可行性数据，该R 01旨在测试人源性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来获得测试这一中心假设所需的初步数据。在静脉内接种人源纳米颗粒后，将在家兔中定量动脉重塑的程度和质量。将比较纳米颗粒接种与胆固醇喂养和内皮剥脱组合的效果。除了标准组织学技术外，还将使用最先进的低温静态显微计算机断层扫描，其独特优势是以高空间分辨率对高达2 cm 3的组织标本进行成像，而不会通过切片和/或固定剂对其进行破坏。因此，可以对钙化的特定区域进行打孔活检，以进行后续的生化分析和培养。这些实验具有很高的风险，因为尚不清楚人类来源的纳米颗粒是否会导致动脉钙化。然而，需要了解这些人源性纳米颗粒是否以及如何影响血管生物学，以平衡风险。因此，这些实验填补了现有知识的一个重要空白，并具有高影响力的潜力。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。由于纳米颗粒被用于工业和商业目的，因此必须检查其潜在的毒性。人源性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一个重要空白，并具有高影响力的潜力。如果人类来源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，实验可以代表一个范例，以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。