The proposed expansion of the existing Bioengineering Partnership (R01 ES015241) is an effective, broad and interdisciplinary effort to devise novel tools, methods and knowledge that will assist the NIEHS and NTP in protecting human health. We have recruited an outstanding team of experienced scientists in the areas of environmental engineering and atmospheric chemistry, inhalational toxicology, and human models of environmentally-relevant disease. UNC is the only institution in the world that has the multidisciplinary team, facilities, and samplers capable of creating model atmospheres which faithfully reproduce real air, and quantifying their adverse health effects by directly exposing lung cells or animals. The unique advantage of the proposed partnership is existing close interaction both within the team members who are faculty at the Department of Environmental Sciences and Engineering at UNC, and between the UNC and MatTek Corporation investigators. This partnership will test the hypothesis that the risk of air pollution-related lung disease is different for gas- and particulate components present in air pollution mixtures, that physico-chemical processes (e.g., natural sun light, temperature, humidity, etc.) in the atmosphere significantly affects these responses, and that genetics and underlying disease are important determinant for susceptibility. This hypothesis will be tested through three projects. Project 1 will deliver environmental engineering solutions for inhalational toxicology research. We will expose biological tissues and mice to fresh and photochemically aged diesel exhaust alone, or in a multi-pollutant urban mix. Furthermore, we will continue development of the in vitro field-deployable device to improve sensitivity at ambient levels. Project 2 is designed to conduct in vitro and in vivo screening of the effects of "real"-but-model atmospheres in the mouse. We will determine the effects of diesel exhaust gas and gas+PM fractions on mouse tracheal epithelial cells in vitro and mice in vivo, and compare the responses of diesel exhaust in the context of different background atmospheres in vitro and in vivo in the mouse. Project 3 will conduct in vitro screening of the effects of "real"-but-model atmospheres in healthy and asthmatic human-derived organotypic cultures. Specifically, we will determine the effects of diesel exhaust gas and gas+PM fractions on organotypic human tracheal epithelial cultures in vitro, and compare the responses of in vitro organotypic human cultures to diesel exhaust in the context of different background atmospheres. The data and knowledge that will be generated will have an impact through its ability to provide a bridge between lab-based research on toxicity mechanisms and human epidemiological studies by providing a tool that can be applied to "real" world atmospheres, and can differentiate between various components of the complex mixtures of the pollutants.
There is an undisputed link between air pollution and adverse effects on human health, especially lung disease. It is difficult, however, to study the effects of air pollution as it is a complex mixture of gases and particulate matter which undergoes complex physico-chemical changes due to sunlight, humidity, etc. Our interdisciplinary team has developed a novel in vitro exposure system to help address limitations of the existing inhalational toxicology model systems and this proposal is concerned with demonstrating the utility of the device with human and mouse cell cultures, and comparing the data to results from whole animals, after exposure to real life atmospheres.
|Uehara, Takeki; Pogribny, Igor P; Rusyn, Ivan (2014) The DEN and CCl4 -Induced Mouse Model of Fibrosis and Inflammation-Associated Hepatocellular Carcinoma. Curr Protoc Pharmacol 66:14.30.1-14.30.10|
|Chiu, Weihsueh A; Campbell Jr, Jerry L; Clewell 3rd, Harvey J et al. (2014) Physiologically based pharmacokinetic (PBPK) modeling of interstrain variability in trichloroethylene metabolism in the mouse. Environ Health Perspect 122:456-63|
|Buck, Lorenna D; Inman, S Walker; Rusyn, Ivan et al. (2014) Co-regulation of primary mouse hepatocyte viability and function by oxygen and matrix. Biotechnol Bioeng 111:1018-27|
|Rusyn, Ivan; Lemon, Stanley M (2014) Mechanisms of HCV-induced liver cancer: what did we learn from in vitro and animal studies? Cancer Lett 345:210-5|
|Ebrahimkhani, Mohammad R; Neiman, Jaclyn A Shepard; Raredon, Micha Sam B et al. (2014) Bioreactor technologies to support liver function in vitro. Adv Drug Deliv Rev 69-70:132-57|
|Sirenko, Oksana; Hesley, Jayne; Rusyn, Ivan et al. (2014) High-content assays for hepatotoxicity using induced pluripotent stem cell-derived cells. Assay Drug Dev Technol 12:43-54|
|Pogribny, Igor P; Rusyn, Ivan (2014) Role of epigenetic aberrations in the development and progression of human hepatocellular carcinoma. Cancer Lett 342:223-30|
|Chappell, Grace; Kutanzi, Kristy; Uehara, Takeki et al. (2014) Genetic and epigenetic changes in fibrosis-associated hepatocarcinogenesis in mice. Int J Cancer 134:2778-88|
|Low, Yen Sia; Sedykh, Alexander Yeugenyevich; Rusyn, Ivan et al. (2014) Integrative approaches for predicting in vivo effects of chemicals from their structural descriptors and the results of short-term biological assays. Curr Top Med Chem 14:1356-64|
|Zavala, Jose; Lichtveld, Kim; Ebersviller, Seth et al. (2014) The Gillings Sampler--an electrostatic air sampler as an alternative method for aerosol in vitro exposure studies. Chem Biol Interact 220:158-68|
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