Intranasal Insulin Therapy for HIV-Associated Neurocognitive Disorders: Preclinical Evaluation

项目总结 手仍然是慢性艾滋病毒感染最令人虚弱的特征之一，尽管它几乎是普遍使用的 抗逆转录病毒治疗在控制艾滋病毒复制和预防免疫缺陷方面的成功和 艾滋病。手部的病理生理机制还不是很清楚，也没有有效的治疗方法。 治疗。越来越多的证据支持胰岛素介导的信号通路是正常 认知过程。胰岛素信号转导失调与炎症过程和能量有关 新陈代谢与包括手部在内的几种神经退行性疾病的发病机制有关。 最近的临床研究表明，经鼻腔将胰岛素输送到中枢神经系统可增强认知过程 在正常、阿尔茨海默氏症和糖尿病患者中。P01的总体假设是慢性鼻腔胰岛素 给药也可能在改善手部认知缺陷方面有效。在这个项目中，我们将探索这一点 通过测试鼻内注射胰岛素是否剂量依赖性地增加大脑进行临床前假说 胰岛素水平，并减轻手部感染EcoHIV小鼠模型的认知和组织学缺陷 抗病毒疗法。我们还将监测能量代谢、血脂谱、胰岛素信号转导，并选择 神经炎症的标记物。总的来说，这些数据将为胰岛素脑暴露提供指导，并 利用胰岛素脑的新信息探索手部临床研究中的生物标记物 指示胰岛素疗效的脑脊液标志物的药代动力学和特性。这样的暴露-反应 生物标记物数据可能会被证明是有用的，包括未来在代谢和其他方面的研究 神经退行性疾病。

PROJECT SUMMARY HAND remains among the most debilitating features of chronic infection with HIV, despite almost universal use of and success of antiretroviral therapy in controlling HIV replication and preventing immunodeficiency and AIDS. The pathophysiological mechanisms of HAND are not well understood, and there are no effective treatments. Growing evidence supports insulin-mediated signaling pathways as key components in normal cognitive processes. Dysregulation of insulin signaling is implicated in inflammatory processes and energy metabolism and associated with the pathogenesis of several neurodegenerative diseases, including HAND. Recent clinical studies have shown that intranasal delivery of insulin to the CNS enhances cognitive processes in normal, Alzheimer’s and diabetic patients. The overall hypothesis of this P01 is that chronic intranasal insulin administration may also be effective in improving cognitive deficits in HAND. In this project we will explore this hypothesis preclinically by testing whether intranasal insulin administration dose dependently increases brain insulin levels, and attenuates cognitive and histological deficits in the EcoHIV murine model of HAND with antivetroviral therapy. We will also monitor energy metabolism, lipid profiles, insulin signaling, and selected markers of neuroinflammation. Collectively these data will provide guidance on the insulin brain exposure and biomarker exploration in the HAND clinical investigations through new information on insulin brain pharmacokinetics and characterization of CSF markers indicative of insulin efficacy. Such exposure-response and biomarker data may prove useful beyond HAND, including future studies in metabolic and other neurodegenerative diseases.