Molecular and Cellular Biology; Neurodegenerative disorders; Transcription and Translation; Signal Transduction; Toxicology and Xenobiotics
My lab studies the receptor signaling mechanisms for a family of neurotrophic factors that includes ciliary neurotrophic factor (CNTF), leptin, interferon gamma, and cardiotrophin-1. These factors use the Jak/STAT pathway to regulate neuronal survival, development and response to trauma. Our interests are in how activity of the receptors and their pathway components are regulated. Currently this has focused on the impact of cellular oxidative stress on the inhibition of Jak tyrosine kinase activity. Increases in oxidative stress in neurons result in the blockade of not only CNTF family factor effects, but of many other cytokines that also use the Jak/STAT pathway for signaling such as interferons and interleukins. Non-nerve cells appear resistant to these effects of oxidative stress. Ongoing projects include testing the theory that environmental contaminants known to increase oxidative stress in cells may promote neurodegenerative diseases by inhibiting growth factor signaling. We have been studying the effects of certain heavy metals (cadmium & mercury) and pesticides (e.g. rotenone) on nerve cells in culture to determine the molecular basis for Jak inhibition. Another examines a possible role of oxidative stress in obesity. This study tests the hypothesis that the loss of the ability of the hormone leptin to regulate metabolism and appetite during obesity is a result of oxidative reactions that inhibit Jak-mediated signaling in the hypothalamus and other brain regions.
Neurodegenerative disorders; Apoptosis and cell death; Membrane Transport (Ion Transport); Proteins and metalloenzymes; Signal Transduction; Toxicology and Xenobiotics
Dr. Jerome Roth‘s research interests over the past several years have focused on the mechanism of action of manganese in producing neuronal cell death. Manganese is an essential mineral that at high concentration acts as a neurotoxin which produces a Parkinson-like syndrome. Although the identified brain lesions associated with manganism differ from those of Parkinson’s disease, there is increasing evidence that chronic exposure to Mn correlates with increased susceptibility to develop Parkinsonism. Current studies are focused on characterizing the signal transduction pathways stimulated by manganese and to determine whether they also play a role in the toxic actions of this divalent cation. As part of this project we are also investigating the transport mechanisms by which manganese is taken up into cells. We have focused our studies on the divalent metal transporter (DMT1) and its role in the transport of manganese and other divalent cations. We are currently studying the transcriptional and post-translational factors that regulate its expression in vivo. Preliminary studies have linked DMT1 expression to the protein, parkin, mutations in which lead to early onset of Parkinson‘s disease. Whether other gene linked to Parkinsonism are also associate with development of manganism is the current focus of my research. Current studies in my laboratory focus on how other early and late genes associated with Parkinson’s disease can influence Mn toxicity as these studies will provide a basis for the comorbidity between manganism and Parkinson’s; the manipulation of this mechanism may therefore provide new prophylactic and/or management treatment options for Parkinson’s disease.
Genomics and proteomics; Neurobiology; Neurodegenerative disorders
My lab investigates the molecular control of cell fate and homeostasis of resident stem and progenitor cells in the human brain. Using a combination of multicolor cell sorting techniques and whole genome analysis, we are characterizing the signaling pathways which regulate the formation and fate of human oligodendrocyte progenitor cells. We are testing the functional significance of these pathways using both pharmacological and viral methods in culture and animal-based models of myelination and demyelination.