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）：作为组织保护剂的新型免疫调节剂体内的组织可能因多种事件而受损。在施加破坏性刺激后保护这些组织是一个有价值的目标。文献中的一些报告表明，缺乏 APOE 基因的小鼠（APOE 敲除小鼠）因此缺乏载脂蛋白-E（apoE 蛋白），在受到细菌攻击后比含有 apoE 的野生型小鼠更容易死亡。我们现在在此报告，缺乏apoE蛋白的APOE基因敲除小鼠对全身辐射更加敏感，并且在其野生型、含有apoE的对应物存活的辐射剂量下死亡。这开启了apoE蛋白或apoE蛋白模拟物可用于保护组织免受辐射破坏作用的可能性。我们正在开发 COG133，这是一种基于载脂蛋白-E (apoE) 残基 133-149 的肽。 COG133 在基于细胞的炎症模型和整个动物炎症模型中显示出抗炎活性。我们最近报道，用脂多糖加 COG133 治疗的 C57Bl/6 小鼠的细胞因子释放明显低于仅用脂多糖治疗的小鼠（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 的全身辐射，然后用 COG133 治疗，其存活时间明显长于用盐水治疗的小鼠。结合我们关于 APOE 基因敲除小鼠对电离辐射敏感性的新数据，我们将充分检验 COG133 可以保护小鼠免受全身辐射对死亡率的有害和致命影响的假设。作为组织保护剂的新型免疫调节剂：全身暴露于高水平电离辐射通常会导致生命终结（Hall 2000）。即使暴露于有限水平的电离辐射也会导致显着的发病率并可能导致死亡。医疗环境中的受控全身照射（TBI）对于某些癌症治疗方式是有益的，但仍然与严重和不需要的副作用相关。无论是事故、放射性分散装置的悲惨袭击（NIAID 专家组白皮书，2003 年）、太空旅行还是预定的医疗程序；医疗界迫切需要能够显着降低或消除全身照射 (TBI) 相关发病率和死亡率的治疗方法。