Engineered nanomaterials (ENM) have great therapeutic potential but their biological interactions are still largely unknown. Previous studies have shown that ENM are capable of inducing microvascular dysfunction but its currently unknown if this dysfunction is due to direct ENM contact or alterations in circulating factors (i.e. chemokines and cytokines) in the plasma. Finally, with the increasing use of ENM in commercial and therapeutic products, there is an immediate need to create high-throughput screening methods to identify endothelial toxicity associated with ENMs. This proposal aims to use a novel approach, which applies ?omic? approaches to better understand the microvascular dysfunction and toxicity associated with ENM. Therefore, we hypothesize that the physicochemical properties of engineered nanomaterials contribute to unique proteomic and transcriptomic profiles in the vascular system, which direct the observed microvascular dysfunction. This hypothesis will be tested using two specific aims, consisting of in vitro and in vivo techniques. The goal of Aim 1 is to analyze the influences of the physicochemical properties of ENM on microvascular dysfunction. Furthermore, this aim will analyze the ability of secondary circulating factors (i.e. chemokines and cytokines) to induce microvascular dysfunction in an ex vivo setting. The ENM used in this aim will be modified to induce electronic defects, which will alter their ability to transfer and accept electrons when in a biological environment and ultimately affect their toxicity. These ENM will be screened using in vitro techniques to analyze endothelial toxicity and identify the ENMs with the lowest and highest toxicity. After these ENM are identified, mice will be intravenously injected to analyze the microvascular dysfunction associated with these ENM. Plasma will be collected from the mice following exposure and used to treat nave arterioles. We predict that this treatment will induce microvascular dysfunction due to the changes in circulating chemokines and cytokines. These assessments will help to determine if direct ENM contact or secondary circulating factors are the leading cause of microvascular dysfunction following ENM exposure.
The second aim will utilize a transciptome-proteome approach to quantitatively identify changes in circulating proteins and their subsequent downstream effects on transcriptomic responses in the microvasculature. The use of bioinformatics to integrate exposure changes at both the transcript and protein level will provide a unique analysis of microvascular dysfunction, which will aid in the identification of biomarkers for high-throughput screening methods and the mechanism of action for ENM induced microvascular dysfunction.

Public Health Relevance

Engineered nanomaterial (ENM) exposure is commonly associated with microvascular dysfunction, which is an early predictive marker for chronic disease development (i.e. hypertension). We believe this dysfunction is dependent on the physicochemical properties of the ENM and is initiated by secondary circulating factors (i.e. chemokines and cytokines) in the plasma and not direct ENM interaction. This project is designed to test this hypothesis using a novel approach, which applies bioinformatic integration of proteomic and transcriptomic data.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1)
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Nadadur, Srikanth
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University of Colorado Denver
Schools of Pharmacy
United States
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