Treatment of EAE by Small Peptide Mimetics of SOCS-1

描述（由申请人提供）：细胞因子信号抑制因子（SOCS）在正常的体内平衡功能中起着不可或缺的作用。例如，敲除小鼠体内的SOCS-1基因会导致胚胎致死。致死率已被证明是由于γ干扰素活性不受管制。SOCS-1通过结合酪氨酸激酶JAK2的自磷酸化位点抑制细胞因子，如IFN功能。我们开发了一种短肽WLVFFVIFYFFR，它特异性地结合JAK2的自磷酸化位点，导致其自磷酸化抑制，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相似的功能。我们拟在多发性硬化症实验性变应性脑脊髓炎（EAE）小鼠模型中验证酪氨酸激酶抑制肽（Tkip）具有抗炎作用的假设。我们将通过以下具体目标来验证这一假设，并特别关注免疫机制。1. 确定Tkip及其变异对NZW和C57BL/6小鼠急性EAE的保护能力。2. 确定Tkip及其变体保护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. 确定Tkip及其变体通过超抗原阻断EAE再激活的能力。4. 细胞穿透型SOCS-1重组蛋白治疗EAE的疗效观察。这里提出的研究直接关系到天然不可或缺的宿主调节系统对抗自身免疫以及其他基本功能。因此，这是一种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.