Cytokine Regulation of Photoreceptor Gene Expression

描述（由申请人提供）：本提案是根据编号为no - od -09-058的通知提出的，标题为：NIH宣布为竞争性修订申请提供恢复法案资金。因此，该申请旨在修改当前资助的项目EY016459。神经细胞因子在预防或延缓神经变性方面显示出巨大的治疗潜力，包括引起视网膜色素变性和干性黄斑变性的神经变性。白血病抑制因子（LIF）和纤毛神经营养因子（CNTF）的广谱保护活性在基因突变或环境因素多样或未知时具有明显的治疗优势。由于这一优势，CNTF正在进行II期临床试验，以防止色素性视网膜炎（RP）患者的光受体细胞死亡。几乎所有的药物都有意想不到的副作用，这些副作用通常在药物使用远远超过其治疗范围时表现出来。不幸的是，在高浓度下，CNTF和LIF具有减少光感受器功能的不良副作用，从而可能限制其治疗价值。LIF与CNTF不同源，但在功能上是相关的。我们的研究表明，中等剂量的LIF具有保护作用，而不会在5倍范围内降低功能，从而建立了较大的治疗范围。在高剂量时，LIF抑制功能。高浓度对功能的抑制是未来治疗的障碍，并可能限制分子的有用性。我们希望通过确定LIF诱导生存的机制及其抑制功能的机制，进一步完善LIF的治疗价值。这将使我们能够开发出新的疗法，在不抑制功能的情况下提供广谱保护。细胞内靶标的识别将为小分子的开发开辟道路，这些小分子可以用来代替体积大、不稳定的蛋白质。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.