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.
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