Project description:Vinylidene Chloride has been widely used in the production of plastics and flame retardants. Exposure of B6C3F1 to VDC in the 2-year National Toxicology Program carcinogenicity bioassay resulted in a dose-dependent increase in renal cell hyperplasias, adenomas, and carcinomas (RCCs). Global gene expression analysis showed overrepresentation of pathways associated with chronic xenobiotic and oxidative stress in RCCs from VDC-exposed B6C3F1 mice, as well as cMyc overexpression and dysregulation of Tp53 cell cycle checkpoint and DNA damage repair pathways. Trend analysis comparing RCC, VDC-exposed kidney, and vehicle control kidney showed a conservation of pathway dysregulation in terms of overrepresentation of xenobiotic and oxidative stress, and DNA damage and cell cycle checkpoint pathways in both VDC-exposed kidney and RCC, suggesting that these mechanisms play a role in the development of RCC in VDC-exposed mice. Compare mouse renal cell carcinoma versus treated kidney and vehicle control normal kidney, 6 replicates each group.
Project description:Physiologically relevant cellular models are critical for understanding complex pathological processes. Parkinsonâs disease (PD) is the second most common neurodegenerative disorder characterised by motor and non-motor symptoms. Several cellular models for PD have been developed to reproduce the abberant biochemical pathways associated with Parkinsonâs disease such as oxidative stress, apoptosis, improper clearance of misfolded proteins and mitochondrial impairment. However, there is still a need for models that effectively recapitulate pathological phenotypes of PD. We previously reported that cells derived from the olfactory epithelium of idiopathic PD patients have altered cellular functions compared with age and gender-matched healthy controls. We also identified an underlying dysregulation of molecular pathways including the Nrf2 pathway in PD hONS cells. Here, we tested the hypothesis that hONS cells derived from PD patients are more vulnerable to extrinsic stressors. We identified that PD-hONS cells are particularly sensitive to mitochondrial and oxidative stress. Notably, PD hONS cells exposed to Rotenone undergo significant apoptosis, show reduced mitochondrial complex I activity and reduced induction of Heat Shock Protein HSP27.
Project description:Description: We find multiple evidence that mitochondria are directly and indirectly involved in the pathologic activation of cellular innate immunity. Previously, studies have shown that pathologic type I interferon signatures promote autoimmune diseases and noted mitochondrial and mtDNA dysregulation in chronic inflammatory diseases. Based upon previous data from our lab and others, we anticipated a direct link between the mitochondrial dysfunction and the elevated production of type I interferon or the increase of other innate immune signatures in chronic and general inflammatory diseases. In this project, we wished to test our overall hypothesis that inhibition of mtDNA-mediated immune activation pathway is a promising pharmacological target for chronic inflammatory diseases. To pursue this goal, we developed a murine conditional knockout model, where kidney epithelial cells show dysfunctioning mitochondrial phenotype, and verified that this mouse model has lethal kidney failure with features of chronic kidney disease. By using systems biology approaches, we aimed to examine which genes are regulated in the kidney with dysfunctioning mitochondrial phenotype and identify the main pathways leading to the chronic autoimmune disease. Results: We found that interferon-stimulated genes are upregulated in Cox10 mouse kidney. Likely, mitochondrial dysregulation and mtDNA release induces expression of genes known as interferon-stimulated genes (IGS) (West et al., Nature 2015).