Treatment of EAE by Small Peptide Mimetics of SOCS-1

描述（由申请人提供）：细胞因子信号传导抑制因子（SOCS）在正常稳态功能中发挥不可或缺的作用。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。SOCS-1通过与酪氨酸激酶JAK 2的自磷酸化位点结合来抑制细胞因子如IFN功能。我们已经开发了一种短的12-mer肽，WLVFFVIFYFFR，其特异性结合JAK 2的自磷酸化位点，导致其自磷酸化的抑制以及受体亚基IFNGR-1和转录因子STAT 1的磷酸化。因此，该肽具有与SOCS-1类似的功能。我们建议测试的假设，酪氨酸激酶抑制肽（Tkip）具有抗炎作用的实验性过敏性脑脊髓炎（EAE）多发性硬化症的小鼠模型。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和变体保护NZW和C57 BL/6小鼠免受急性EAE的能力。2.确定Tkip和变体保护SJL/J小鼠免受髓鞘碱性蛋白诱导和再激活复发/缓解型EAE的能力。3.测定Tkip和变体阻断EAE通过超抗原再活化的能力。4. SOCS-1重组蛋白的细胞穿透形式在治疗EAE中的治疗效果。这里提出的研究直接关系到一个自然的不可或缺的宿主调节系统对自身免疫以及其他基本功能。因此，这是治疗和预防免疫性疾病的新方法。

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.