Cytokine Regulation of Photoreceptor Gene Expression

光感受器基因表达的细胞因子调节

• 批准号: 7846053
• 负责人: John D Ash
• 金额: $ 36.63万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2010-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7846053
• 关键词: Adverse effects; Antibodies; Blindness; Candidate Disease Gene; Cell Death; Cell Proliferation; Cell Survival; Cells; Ciliary Neurotrophic Factor; Clinical Trials; DNA; DNA Microarray Chip; Data; Development; Disease; Dose; Drug usage; Environmental Risk Factor; Family; Funding; Future; Gene Expression; Gene Mutation; Genes; Goals; Inherited; Injection of therapeutic agent; Knock-out; Knockout Mice; Knowledge; Light; Macular degeneration; Measures; Mediating; Mus; Mutation; Nerve Degeneration; Neurologic; Oncogenes; PIM1 gene; Pathway interactions; Patients; Pharmaceutical Preparations; Phase II Clinical Trials; Phosphotransferases; Photoreceptors; Play; Protein-Serine-Threonine Kinases; Proteins; RNA analysis; Recovery; Regulation; Retina; Retinal Degeneration; Retinitis Pigmentosa; Role; STAT3 gene; Serine; Signal Pathway; System; Testing; Therapeutic; Time; United States; United States National Institutes of Health; Up-Regulation; Work; age related; base; cancer cell; cytokine; cytokine receptor gp130; design; dosage; inherited retinal degeneration; leukemia inhibitory factor; member; neoplastic cell; neuroprotection; overexpression; prevent; public health relevance; response; retinal neuron; retinal rods; small molecule; transcription factor

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.

描述（由申请人提供）：本提案是针对编号为 NOT-OD-09-058 的通知而提出的，标题为：NIH 宣布恢复法案基金可用于竞争性修订申请。因此，本申请旨在修订当前资助的项目 EY016459。神经细胞因子已显示出预防或延缓神经变性的巨大治疗潜力，包括引起色素性视网膜炎和干性黄斑变性的神经变性。白血病抑制因子（LIF）和睫状神经营养因子（CNTF）的广谱保护活性在基因突变或环境因素多样或未知的情况下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，以预防色素性视网膜炎 (RP) 患者的感光细胞死亡。几乎所有药物都有不良副作用，这些副作用通常在药物使用远高于其治疗范围时显现出来。不幸的是，在高浓度下，CNTF 和 LIF 会产生降低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，但功能相关。我们的研究表明，中等剂量的 LIF 具有保护作用，且功能不会降低 5 倍以上，从而建立了较大的治疗范围。较高剂量的 LIF 会抑制功能。高浓度下的功能抑制是未来治疗的障碍，并可能限制分子的用途。我们希望通过确定 LIF 诱导存活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。细胞内靶标的鉴定将为开发小分子开辟途径，这些小分子可以用来代替庞大且不稳定的蛋白质。 公共健康相关性：神经细胞因子已显示出预防或延迟神经变性的巨大治疗潜力，包括引起色素性视网膜炎和干性黄斑变性的神经变性。当导致疾病的基因突变或环境因素多样或未知时，睫状神经营养因子（CNTF）的广谱保护活性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，以预防色素性视网膜炎 (RP) 患者的感光细胞死亡。几乎所有药物都有不良副作用，这些副作用通常在药物使用远高于其治疗范围时显现出来。不幸的是，在高浓度下，CNTF 会产生降低光感受器功能的不良副作用，从而可能限制其治疗价值。 白血病抑制因子 (LIF) 与 CNTF 不同源，但功能相关。我们的研究表明，LIF 在 5 倍剂量范围内可提供细胞死亡保护，且不会降低光感受器功能。然而，当LIF以高浓度应用时，高浓度的功能抑制已导致严重的不良后果。预计这将成为未来治疗的障碍，并可能限制这一重要分子的用途。该项目的目标之一是通过确定 LIF 诱导存活的机制及其抑制功能的机制，进一步明确 LIF 的治疗价值。这些知识将有助于开发新疗法，在不抑制功能的情况下提供广谱保护。细胞内靶标的鉴定将为开发小分子开辟途径，这些小分子可以用来代替庞大且不稳定的蛋白质。我们和其他人已经确定 STAT3 是保护所需的 LIF 下游转录因子。本次修订的具体目的是确定受 LIF 调节且特别需要 STAT3 的基因。这将确定 LIF 诱导保护的机制。我们在前期工作中确定的一个候选基因是 PIM 丝氨酸/苏氨酸激酶家族的成员。我们将使用这些激酶的基因敲除小鼠来确定它们是否对于 LIF 诱导的保护至关重要。