Treatment of EAE by Small Peptide Mimetics of SOCS-1

描述(申请人提供)：细胞因子信号转导抑制物(SOCs)在正常的体内平衡功能中起着不可或缺的作用。例如，敲除小鼠的SoCS-1基因会导致胚胎死亡。致命性已被证明是由于不受控制的伽马干扰素活动造成的。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，如干扰素的功能。我们开发了一个短小的12肽，WLVFFVIFYFFR，它特异性地结合JAK2的自磷酸化位点，从而抑制其自磷酸化，以及受体亚单位IFNGR-1和转录因子STAT1的磷酸化。因此，该多肽具有与SOCS-1类似的功能。我们建议在实验性变态反应性脑脊髓炎(EAE)多发性硬化症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检验这一假说，并特别关注免疫学机制。1.检测TKIP及其变异体对NZW和C57BL/6小鼠急性EAE的保护作用。2.检测TKIP及其突变体对髓鞘碱性蛋白诱导和再激活SJL/J小鼠复发/缓解性EAE的保护作用。3.检测TKIP及其变异体通过超抗原阻断EAE再激活的能力。4.细胞穿透型SOCS-1重组蛋白治疗EAE的疗效这里提出的研究直接涉及针对自身免疫的一个天然的、不可或缺的宿主调节系统以及其他基本功能。因此，这是治疗和预防免疫性疾病的一种新方法。

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.