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修饰剂体内的组织可能会因各种事件而受损。在施加损伤性刺激后保护这些组织是一个值得追求的目标。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），在细菌攻击后比其野生型，含apoE的对应物更容易死亡。我们现在在此报道，缺乏apoE蛋白的APOE敲除小鼠对全身辐射明显更敏感，并且在其野生型含apoE的对应物生活的辐射剂量下死亡。这开启了apoE蛋白或apoE蛋白的模拟物可用于保护组织免受辐射损伤的可能性。我们正在开发COG 133，一种基于载脂蛋白E（apoE）残基133-149的肽。COG 133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COG 133处理的C57 B1/6小鼠比单独用脂多糖处理的小鼠具有显著更少的细胞因子释放（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戈伊的全身照射，然后用COG 133治疗，存活时间显着长于盐水治疗的对应物。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，我们将充分验证COG 133可能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。新型免疫修饰剂作为组织保护剂：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造成严重的发病率，并可能导致死亡。在医疗环境中的受控全身照射（TBI）在某些癌症治疗方式中是有益的，但仍然与严重和不希望的副作用相关。无论是事故、放射性弥散装置的悲惨袭击（NIAID小组白色文件，2003年）、太空旅行还是预定的医疗程序;都存在对能够显著降低或消除与全身照射（TBI）相关的发病率和死亡率的治疗的巨大医疗需求。