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RESEARCH

Basic Research | Translational Research

Basic Research

Antioxidant signaling

The Keap1/Nrf2/ARE pathwaymediates the inducible “programmed cell life” response (the coordinated expression of a battery ofantioxidant and phase II detoxification enzymes) in a number of different tissues, including the brain and skeletal muscle. In worms and flies, elevated Nrf2 activity results in increased resistance to oxidative stress andextension oflifespan. However, aberrant activation of the Nrf2 pathway can also have negative consequences. For example, elevated Nrf2 activity promotes tumorigenesis and is associated with a loss of glucose-stimulated insulin secretion.Furthermore, increased expression of the Nrf2-regulated antioxidant enzymes leads to “reductive stress” and protein aggregation cardiomyopathy in transgenic mice that express mutant form of human αB-crystallin. Thus, the optimal level of Nrf2 activity – which varies among different cell types – must be tightly regulated. However, little is known about intrinsic physiologic and metabolic signals that regulate Nrf2 activity in the absence of extrinsic oxidative or toxic stress.

At high doses, reactive oxygen species (ROS) damage cellular macromolecules and lead to cellular injury and death. At low doses, however, some ROS (such as H2O2) regulate normal cellular processes, such as activity of ion Specific questions we are currently addressing (or plan to address in the future) include:

Autophagy

Autophagy is a conserved mechanism for degradation of cytoplasmic components,which at baseline contributes to cellular homeostasisbyenabling routine protein and organelle turnover through lysosomal degradation. Autophagy dysfunction has been linked to a numberofage-associated diseases including cancer, neurodegeneration, and inclusion body myositis (and age-associated skeletal myopathy). Recent work has also established a link between autophagy and the Keap1/Nrf2 pathway. p62 – an adapter protein that targets ubiquitinated protein aggregates for lysosomal degradation and accumulates following autophagy inhibition – competes with Nrf2 for Keap1 binding; through p62 accumulation, autophagy impairment thus leads to nuclear translocation of Nrf2 and increased expression of the Nrf2 target genes.

In animal models, autophagy deficiency results in neurodegeneration and skeletal muscle atrophy; little, however, is known about the role of autophagy in normal neurologic function. Our lab seeks to elucidate several questions:

Translational Research

The goal of our translational research is to improve tissue-based diagnostics of neurologic disorders. To achieve this goal, we use a two-pronged approach: (1) clinico-pathologic analysis of single cases or series of cases to elucidate the relationship between related disorders and refine their diagnostic criteria; and (2) immunohistochemical and/or biochemical analyses of autopsy and biopsy-derived human tissue specimens to develop new or improved diagnostic tools.

Current projects are addressing several different questions: