The last decade has witnessed rapid growth in the nanotechnology industry: more than 1,000 consumer products containing nanoparticles (NPs) are currently in the market place, and a variety of newly engineered nanomaterials are developed every day. As a result, workers in the nanotechnology industry, consumers, and ultimately the environment itself inevitably come in contact with engineered NPs. Because of their unique properties, including their nanoscale size, large surface area, chemical composition, and reactivity, NPs interact with biological components and systems, many of which also operate at the nanoscale level. Not surprisingly, growing concerns have been raised over the possibility that these interactions could have deleterious effects on humans. Currently, toxicology studies are typically conducted to assess the risk associated with exposure to newly engineered nanomaterials. However, even when NPs are not deemed toxic based on standard in vivo and in vitro viability assays, they might still significantly alter cell physiology. A wealth of information is available about the cellular uptake of NPs, and the rate at which cells internalize NPs can be controlled with respect to NP size, charge, and surface properties. However, the impact of these physicochemical properties on other cellular processes has not been investigated in a systematic fashion. It is known, for instance, that upon internalization, most NPs elicit the reaction of cellular clearance mechanisms. Indeed, the project team recently found that a number of NPs activate autophagy, the main catabolic pathway that eliminates cellular waste. While activation of autophagy may lead to enhanced clearance of waste material, it can also induce activation of cell death programs. Moreover, preliminary studies indicate that NPs of specific charege and composition can activate the autophagic response but also impair cellular components that mediate degradation, ultimately blocking autophagic flux. The project team recently developed a set of analytical tools to monitor the autophagic flux and cell model systems to measure the accumulation of autophagic substrates, including proteolipid and proteinaceous aggregates. The team is thus uniquely positioned to investigate the impact of NPs on the autophagic system. The overarching goal of the proposed project is to map the physicochemical properties of NPs with the nature of the autophagic response that they induce, ultimately generating the design rules to engineer NPs with the desired properties at the interface with the autophagy system. To achieve this goal, we propose to pursue three research objectives: 1) Identify the physicochemical properties of NPs that activate autophagy; 2) link the physicochemical properties of NPs to biocompatible and bioadverse cellular responses associated with autophagy activation; and 3) identify the cellular network that regulates the autophagic response to NPs.
Intellectual Merit : Results from this study will provide a detailed characterization of the impact of NPs on the autophagy system. The project will establish the effect of NP physicochemical properties, namely geometric parameters, charge, and composition, on downstream effects associated with activation of autophagy, namely clearance of NPs and other autophagic substrates or autophagy-associated cell death. The project will also identify the gene network that regulates the autophagic response to NPs and cellular markers of NP-induced autophagy, thus providing important predictive tools to assess the impact of NPs on cell physiology.
Broader Impacts : This study will generate an experimental framework for investigating the impact of NPs on biological systems. Specially designed reporter systems will be developed and validated to link the physicochemical properties of NPs to cellular responses and their underlying molecular mechanisms. Understanding the impact of NPs on cell physiology, in turn, will contribute to the development of safe nanomaterials and will enable the design of third-generation NPs with tunable properties where these NPs interface with biological systems. Finally, the proposed project will provide novel tools for cellular and molecular biology studies. This research program will also provide broadly reaching educational and training opportunities with the overall goal of increasing the number and diversity of underrepresented groups in STEM. Specifically, this research program will be leveraged 1) to provide research and mentoring opportunities for high school students, and 2) to improve teaching and learning for college students.
