Novel Immunological Modifer as a Tissue Protector

作为组织保护剂的新型免疫调节剂

• 批准号: 7154922
• 负责人: MICHAEL PETER VITEK
• 金额: $ 12.74万
• 依托单位: COGNOSCI, INC.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-15 至 2008-02-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7154922
• 关键词: analog; apolipoprotein E; death; genetically modified animals; inflammation; ionizing radiation; laboratory mouse; lead; lipopolysaccharides; model; neoplasm /cancer; peptides; pharmacokinetics; play; proteins; role; saline; tissues; travel

DESCRIPTION (provided by applicant): Novel Immunological Modifier as a Tissue Protector Tissues in the body can be damaged by a wide variety of events. Protecting these tissues after the damaging stimulus has been applied is a worthy goal. Several reports in the literature have shown that mice lacking the APOE gene (APOE knockout mice) and therefore lacking apolipoprotein-E (apoE protein), are more susceptible to death after a bacterial challenge than their wild-type, apoE-containing counterparts. We now report herein that APOE knockout mice lacking apoE protein are significantly more sensitive to total body irradiation and die at doses of radiation where their wild-type, apoE containing counterparts live. This opens the possibility that apoE protein, or mimetics of apoE protein, might be used to protect tissues from the damaging effects of radiation. We are developing COG133, a peptide based on residues 133-149 of apolipoprotein-E (apoE). COG133 displays anti-inflammatory activities in cell-based models of inflammation and in whole animal models of inflammation. We recently reported that C57Bl/6 mice treated with lipopolysaccharide plus COG133 has significantly less cytokine release than mice treated with lipopolysaccharide alone (Lynch et al. JBC 2003). We report new data in which wild-type mice exposed to 10 Gy of total body irradiation and then treated with COG133, survive significantly longer than their saline treated counterparts. Together with our new data on sensitivity of APOE knockout mice to ionizing radiation, we will fully test the hypothesis that COG133 may protect mice from the harmful and lethal effects of total body irradiation on mortality. Novel Immunological Modifier as a Tissue Protector: Exposure of the whole body to high levels of ionizing radiation typically constitutes a life-ending event (Hall 2000). Exposure to even limited levels of ionizing radiation can cause significant morbidity and may lead to mortality. Controlled total body irradiation (TBI) in a medical setting is beneficial in certain cancer therapeutic modalities, but is none-the- less associated with severe and unwanted side effects. Whether from an accident, from a tragic attack with a Radiological Dispersion Device (NIAID Panel White Paper, 2003), from space travel or from a scheduled medical procedure; there is a great medical need for treatments that can significantly decrease or eliminate the morbidity and mortality associated with Total Body Irradiation (TBI).

描述（由申请人提供）：新型免疫修饰剂作为体内的组织保护物组织可能会因各种事件而损害。在应用破坏性刺激后保护这些组织是一个值得的目标。文献中的几份报道表明，缺乏APOE基因（APOE基因敲除小鼠），因此缺乏载脂蛋白-E（APOE蛋白），在细菌挑战后比其野生型ApoE，抗ApoE的对应物更容易死亡。现在，我们在此报告说，缺乏APOE蛋白的APOE基因敲除小鼠对全身辐射的敏感性明显更高，并且在辐射剂量下死亡，其野生型，含有对应物的ApoE。这打开了APOE蛋白或APOE蛋白的模拟蛋白的可能性，可用于保护组织免受辐射的破坏作用。我们正在开发基于载脂蛋白-E（APOE）的133-149残基的肽COG133。 COG133在基于细胞的炎症模型和整个动物炎症模型中显示抗炎活性。我们最近报道说，用脂多糖和COG133处理的C57BL/6小鼠的细胞因子释放明显少于单独使用脂多糖处理的小鼠（Lynch等人JBC 2003）。我们报告了新的数据，其中野生型小鼠暴露于10 Gy的总体辐照，然后用COG133处理，其生存的时间明显长于其盐水处理的对应物。加上我们有关APOE敲除小鼠对电离辐射的敏感性的新数据，我们将充分检验以下假设：COG133可以保护小鼠免受全身照射对死亡率的有害和致命作用。新型的免疫修饰符作为组织保护器：将整个身体暴露于高水平的电离辐射通常构成生命终止事件（Hall 2000）。暴露于有限水平的电离辐射水平可能会导致明显的发病率，并可能导致死亡率。在医疗环境中受控的全身受控（TBI）对某些癌症治疗方式有益，但与严重和不必要的副作用无关。无论是出于事故，从放射线分散装置的悲惨攻击中（Niaid Panel White Paper，2003年），从太空旅行还是从预定的医疗程序中进行；有很大的医疗需要可以显着降低或消除与全身照射（TBI）相关的发病率和死亡率。