Treatment of EAE by Small Peptide Mimetics of SOCS-1

SOCS-1 的小肽模拟物治疗 EAE

• 批准号: 7469505
• 负责人: HOWARD M JOHNSON
• 金额: $ 31.79万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7469505
• 关键词: Acute; Anti-Inflammatory Agents; Anti-inflammatory; Autoimmunity; Binding; C57BL/6 Mouse; Cells; Cytokine Inducible SH2-Containing Protein; Embryo; Encephalomyelitis; Experimental Autoimmune Encephalomyelitis; Genes; Immune System Diseases; Interferon Type II; Interferons; JAK2 gene; Knock-out; Multiple Sclerosis; Mus; Myelin Basic Proteins; Peptides; Phosphorylation; Play; Prevention; Protein Tyrosine Kinase; Recombinant Proteins; Relapse; Role; SJL/J Mouse; STAT1 gene; Site; Superantigens; System; Testing; Therapeutic Effect; Variant; cytokine; mimetics; mouse model; novel strategies; receptor; transcription factor

DESCRIPTION (provided by applicant): Suppressors of cytokine signaling (SOCS) play an indispensable role in normal homeostatic function. Knockout of SOCS-1 gene in mice, for example, results in embryo lethal effects. Lethality has been shown to be due to unregulated gamma interferon activity. SOCS-1 inhibits cytokines, such as IFN function by binding to the autophosphorylation site of the tyrosine kinase JAK2. We have developed a short 12-mer peptide, WLVFFVIFYFFR, which specifically binds to the autophosphorylation site of JAK2, resulting in inhibition of its autophosphorylation as well as it is phosphorylation of receptor subunit IFNGR-1 and transcription factor STAT1. Thus, the peptide possesses functions similar to SOCS-1. We propose to test the hypothesis that the tyrosine kinase inhibitory peptide (Tkip) has anti-inflammatory effects in the experimental allergic encephalomyelitis (EAE) mouse model of multiple sclerosis. We will test this hypothesis via the following Specific Aims with particular focus on immunological mechanisms. 1. Determine ability of Tkip and variants to protect NZW and C57BL/6 mice against acute EAE. 2. Determine ability of Tkip and variants to protect SJL/J mice against induction and reactivation of relapsing/remitting EAE by myelin basic protein. 3. Determine ability of Tkip and variants to block reactivation of EAE via superantigen. 4. Therapeutic effect of cell-penetrating form of SOCS-1 recombinant protein in treatment of EAE. The studies proposed here are directly related to a natural indispensable host regulatory system against autoimmunity as well as other essential functions. As such, this is a novel approach to treatment and prevention of immunological diseases.

描述（由申请人提供）：细胞因子信号传导抑制剂（SOCS）在正常体内平衡功能中发挥着不可或缺的作用。例如，敲除小鼠中的 SOCS-1 基因会导致胚胎致死效应。致死性已被证明是由于不受调节的γ干扰素活性造成的。 SOCS-1 通过与酪氨酸激酶 JAK2 的自磷酸化位点结合来抑制细胞因子，例如 IFN 功能。我们开发了一种短的 12 聚体肽 WLVFFVIFYFFR，它特异性结合 JAK2 的自磷酸化位点，从而抑制其自磷酸化以及受体亚基 IFNGR-1 和转录因子 STAT1 的磷酸化。因此，该肽具有与SOCS-1类似的功能。我们建议在多发性硬化症的实验性过敏性脑脊髓炎 (EAE) 小鼠模型中检验酪氨酸激酶抑制肽 (Tkip) 具有抗炎作用的假设。我们将通过以下具体目标来检验这一假设，特别关注免疫机制。 1. 确定 Tkip 及其变体保护 NZW 和 C57BL/6 小鼠免受急性 EAE 侵害的能力。 2.确定Tkip和变体保护SJL/J小鼠免受髓磷脂碱性蛋白诱导和再激活复发/缓解型EAE的能力。 3. 确定 Tkip 和变体通过超抗原阻断 EAE 重新激活的能力。 4.细胞穿透型SOCS-1重组蛋白治疗EAE的疗效。这里提出的研究与针对自身免疫的天然不可或缺的宿主调节系统以及其他基本功能直接相关。因此，这是一种治疗和预防免疫性疾病的新方法。