This proposal is made in response to notice number NOT-OD-09-058 entitled: NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications. This application is therefore intended to revise the currently funded project EY016459. Neurological cytokines have shown tremendous therapeutic potential for preventing or delaying neurodegenerations, including those causing retinitis pigmentosa and dry macular degeneration. The broad-spectrum protective activity of leukemia inhibitory factor (LIF) and ciliary neurotrophic factor (CNTF) have a clear therapeutic advantage when the genetic mutation or environmental factors are diverse or unknown. Because of this advantage, CNTF is in phase II clinical trials to prevent photoreceptor cell death in patients suffering from retinitis pigmentosa (RP). Almost all drugs have unwanted side effects, which are usually manifested when drugs are used well above their therapeutic range. Unfortunately, at high concentrations, CNTF and LIF have the unwanted side effect of reducing photoreceptor function thus potentially limiting their therapeutic value. LIF is not homologous to CNTF but is functionally related. Our studies have shown that at moderate doses LIF is protective without reducing function over a 5 fold range, thus establishing a large therapeutic range. At higher doses LIF inhibits function. The inhibition of function at high concentrations is an impediment to future therapies and may limit the usefulness of the molecules. We would like to further refine the therapeutic value of LIF by determining the mechanism by which LIF induces survival versus its mechanism for inhibiting function. This would allow us to develop new therapies which would give broad spectrum protection without inhibiting function. The identification of intracellular targets would open the pathway for the development of small molecules that can be used instead of bulky and labile proteins.
Neurological cytokines have shown tremendous therapeutic potential for preventing or delaying neurodegenerations, including those causing retinitis pigmentosa and dry macular degeneration. The broad- spectrum protective activity of ciliary neurotrophic factor (CNTF) has a clear therapeutic advantage when the genetic mutation or environmental factors causing the disease are diverse or unknown. Because of this advantage, CNTF is in phase II clinical trials to prevent photoreceptor cell death in patients suffering from retinitis pigmentosa (RP). Almost all drugs have unwanted side effects, which are usually manifested when drugs are used well above their therapeutic range. Unfortunately, at high concentrations, CNTF has the unwanted side effect of reducing photoreceptor function, thus potentially limiting its therapeutic value. Leukemia inhibitory factor (LIF) is not homologous to CNTF but is functionally related. Our studies have shown that LIF provides protection from cell death without reducing photoreceptor function over a 5-fold range of dosages. Nevertheless, the inhibition of function at high concentrations has resulted in severe adverse consequences when LIF is applied at high concentrations. It is anticipated that this is an impediment to future therapies and may limit the usefulness of this important molecule. One goal of this project is to further define the therapeutic value of LIF by determining the mechanism by which LIF induces survival versus its mechanism for inhibiting function. This knowledge would allow development of new therapies which would give broad spectrum protection without inhibiting function. The identification of intracellular targets would open the pathway for the development of small molecules that can be used instead of bulky and labile proteins. We and others have identified STAT3 as a transcription factor downstream of LIF that is required for protection.
The specific aims of this revision are to identify genes regulated by LIF that specifically require STAT3. This will identify the mechanism by which LIF induces protection. One candidate gene that we have identified in preliminary work is a member of the PIM serine/theronine kinase family. We will use knockout mice for these kinases to determine if they are essential for LIF induced protection.
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