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There is growing body of evidence that many diseases require a systemic treatment approach rather than targeting just a single enzyme or receptor. Neurodegenerative diseases affect a wide spectrum of the population and, in most cases, lead to physical and/or mental incapacity, involving memory, cognition, language and personality. Aging contributes to the development of neurodegeneration by shifting the equilibrium between oxygendependent and independent mechanisms of energy production towards mitochondriagenerated ATP. Mitochondrial capacity degenerates with aging, making cells susceptible to both ischemic and oxidative insults. Although all mechanisms of hypoxic preconditioning are very far from complete understanding, it is clear that cell is equipped with the necessary molecular machinery to respond to the changes in intracellular oxygen content. However, aging significantly compromises this response. Turning on the existent molecular machinery to compensate for hypoxic and oxidative stress may lead to comprehensive and safe therapeutic strategy for age-related neurodegenerative disorders. To restore homeostatic balance destroyed as a result of acute or chronic injury, one needs to activate intrinsic genetic programs silent or insufficiently active in the damaged cells. Activation of cellular defensive systems requires stabilization of corresponding transcription factors which govern expression of cassettes of genes turning on a particular program such as antioxidant, anti-inflammatory, or anti-hypoxic one. Hence, one of the emerging strategies in drug screening becomes a hunt for activators (or inhibitors) of transcription factors. In some cases there is an enzyme responsible for a rate-limiting conversion of a transcription factor, in some not. The well-known and commonly used approach to screening of activators of transcription factors is the use of luciferase gene cloned under the promoter activated by a specified transcription factor. For example, cell-based screening for activators of hypoxia induced factor 1 (HIF1) is performed using HRE (hypoxia response element)-luciferase (Semenza et al 1996), and for Nrf2 – using ARE (antioxidant response element)-luciferase reporter assay (Moehlenkamp & Johnson 1999). Promega has just begun to offer commercially such type of constructs with any desired promoter for research and drug screening purposes.

Novel Approach to High Throughput Screening for Activators of Transcription Factors