Novel Tissue Protector for Subarachnoid Hemorrhage

用于蛛网膜下腔出血的新型组织保护剂

• 批准号: 7053066
• 负责人: SUZANNE E MCKENNA
• 金额: $ 17.17万
• 依托单位: COGNOSCI, INC.
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-28 至 2006-03-25
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7053066
• 关键词: apolipoprotein E; biomimetics; biotechnology; biotherapeutic agent; cardiovascular disorder chemotherapy; combination chemotherapy; disease /disorder model; drug design /synthesis /production; laboratory mouse; medical complication; neuroprotectants; neuropsychological tests; nimodipine; nonhuman therapy evaluation; subarachnoid hemorrhage; vasospasm

DESCRIPTION (provided by applicant): There are approximately 30,000 new cases of aneurysmal subarachnoid hemorrhage (SAH) in this country, making it a significant health care problem. Despite advances in the medical and surgical care of patients with SAH, this condition still has a high morbidity and mortality, with a 30 day mortality of nearly 50%. In order to examine the pathophysiology of vasospasm following SAH and to take advantage of transgenic technology, we recently characterized a murine model of SAH. This model is an extension of the standard monofilament middle cerebral artery occlusion (MCAO) model performed in our lab and by others around the world (Parra et al. 2002). Using this model, we now demonstrate that animals expressing the epsilon 4 isoform of apolipoprotein-E (apoE4) are significantly more impaired on behavioral tests following SAH than their apoES counterparts. This situation is similar to Alzheimer's disease where patients expressing apoE4 are significantly more impaired and have an earlier age of onset than their apoES counterparts. Cognosci has developed novel mimetic peptides of apoE holo-protein which appear to retain the anti-inflammatory and neuroprotective properties of apoE holo-protein. In pilot studies, we show that 1 of these peptides, COG1410, can significantly improve survival when administered following SAH, compared to animals receiving SAH and saline vehicle as a control. Based on these pilot studies, we now wish to fully test the ability of apoE peptide mimetics to inhibit the behavioral and vasospastic deficits that follow experimental application of subarachnoid hemorrhage in a mouse model.

描述（由申请人提供）：该国大约有 30,000 例动脉瘤性蛛网膜下腔出血 (SAH) 新病例，使其成为一个重大的医疗保健问题。尽管 SAH 患者的医疗和外科治疗取得了进步，但该病的发病率和死亡率仍然很高，30 天死亡率接近 50%。为了研究 SAH 后血管痉挛的病理生理学并利用转基因技术，我们最近对 SAH 小鼠模型进行了表征。该模型是我们实验室和世界各地其他实验室执行的标准单丝大脑中动脉闭塞 (MCAO) 模型的延伸（Parra 等人，2002 年）。使用该模型，我们现在证明表达载脂蛋白 E (apoE4) 的 epsilon 4 同工型的动物在 SAH 后的行为测试中比其 apoES 对应物明显更受影响。这种情况与阿尔茨海默病类似，表达 apoE4 的患者比 apoES 患者的受损程度明显更严重，并且发病年龄更早。 Cognosci 开发了新型 apoE 全蛋白模拟肽，其似乎保留了 apoE 全蛋白的抗炎和神经保护特性。在初步研究中，我们表明，与接受 SAH 和盐水载体作为对照的动物相比，其中一种肽 COG1410 在 SAH 后给药可以显着提高生存率。基于这些初步研究，我们现在希望在小鼠模型中充分测试 apoE 肽模拟物抑制蛛网膜下腔出血实验应用后的行为和血管痉挛缺陷的能力。