NSF Award
2413997
Many consumer and medical products (e.g. athletic wear, plastics, cosmetics, and wound dressings) contain engineered silver nanoparticles to prevent bacterial growth. This can result in the contamination of surface waters, wastewaters, and agricultural lands and to chronic low-level exposure of animals from manufacturing and disposal. In addition, nanoparticles can move up the food chain in environmental systems. Silver nanoparticles easily bypass the linings of the gut and lungs and move into organs, including the brain where they stay for many months or more. This means that frequent exposure may lead to accumulation of low levels of nanosilver in the brain. Therefore, it is important to understand how brain function is altered by resident silver nanoparticles at levels lower than those that kill cells. This project will provide insight into how silver nanoparticles interact with the complex biological mechanisms involved in brain cell development and function. Using cells in culture and a simple animal model, the research team will investigate nanosilver interactions with specific proteins to provide a deeper perspective on the consequences that resident silver nanoparticles have on brain cell function. This work will help determine the impacts that chronic nanosilver exposures might have on mechanisms such as learning and neurodegeneration. The activities will be carried out by an undergraduate workforce at a primarily undergraduate institution in Appalachia that has a high proportion of first-generation students. This project will provide students with experience and training for success in postgraduate programs and science careers. <br/><br/>In contrast to tissues like liver, every part of the brain has unique function, and may not be able to compensate for local damage resulting from bioaccumulated silver nanoparticles. Nanosilver exposure disrupts cytoskeletal organization, inhibits neurite dynamics, and alters intracellular signaling pathways in cultured neural cells. Moreover, rats exposed to oral silver nanoparticles exhibited dysregulation of neurogenesis and accumulation of pTau, a hallmark of neurodegeneration. However, the cellular mechanisms targeted by silver nanoparticles to induce these effects are unknown. The overarching objective of this research is to understand the molecular basis of the interaction of silver nanoparticles with cytoskeletal control mechanisms to induce morphological and functional deficits in neural cells. Several lines of evidence identified collapsin response mediator protein-2 (CRMP-2) and its controller glycogen synthase kinase 3β (GSK3β) as candidate targets. First, this project will determine if nanosilver exposure leads to disruption of localization or activation of these key cytoskeletal regulators in cultured neural cells. Then, strains of the nematode worm Caenorhabditis elegans will be used to measure how exposure to nanosilver during development alters morphological development. Strains expressing fluorescent fusion proteins will be used to assess the function of the highly conserved worm homologue of CRMP-2 (UNC-33) and pre-and post-synaptic structural changes in neurons of worms exposed to nanosilver during development. This is important because cytoskeletal control of morphological development is key to synaptic function. Behavioral assays and optogenetics will quantify neural function of whole worms and individual neurons after development upon exposure to silver nanoparticles. Finally, the worm model system will be used to further examine the formation of pTau aggregates in response to silver nanoparticle exposure. This work will offer mechanistic substrates for understanding nanosilver-induced alterations in neural plasticity and development. The project design is optimized for undergraduate researchers with modular and complementary experiments that allow each student to pursue their own project while contributing to the overall goals of the team. The PI will also develop a new Biology Capstone course that will help students develop skills in interpreting scientific data and foster critical assessment of primary science and its coverage in the mainstream media. High school students will participate in these class meetings to promote scientific research as a career path and to recruit students to undergraduate science programs.<br/><br/>This project is jointly funded by the Nanoscale Interactions Program (NI) and the Established Program to Stimulate Competitive Research (EPSCoR).<br/><br/>This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
