'Intranasal Insulin Therapy for HIV- Associated Neurocognitive Disorders'

 描述(由申请人提供)：艾滋病毒相关神经认知障碍(HAND)在艾滋病毒感染者中仍然是一种非常普遍的疾病，尽管联合抗逆转录病毒疗法(CART)具有强大的效果。手的发育是艾滋病毒患者的一个重要治疗问题，影响到生活质量、死亡率和日常功能。目前，尽管进行了25年的研究，但还没有针对HAND的特定治疗方法进入临床实践。这项建议的首要目标是开发一种新的治疗方法，即鼻腔胰岛素，用于治疗艾滋病毒相关的神经认知障碍(HAND)。根据我们的初步研究，我们已经确定这是一个创新的、高潜力的目标。众所周知，HIV感染和CART会引起与胰岛素信号改变相关的血脂分布、葡萄糖稳态和能量代谢的改变。几十年的研究表明，胰岛素在大脑中具有多种作用，调节着许多受HIV感染干扰的神经通路，包括能量代谢、脂质代谢、神经递质通道活性、轴突生长、突触强度和炎症信号，提示胰岛素在HIV感染背景下可能对中枢神经系统起保护作用。在初步实验中，我们发现胰岛素除了抑制小胶质细胞的炎症反应外，还能保护神经元免受包括有毒HIV蛋白在内的各种伤害，以及缺血、氧化、炎症和兴奋毒性的挑战。在传统小鼠感染嵌合HIV(EcoHIV)所产生的手部新动物模型中，我们发现鼻内注射胰岛素治疗9天可完全逆转感染动物的认知功能障碍。这些数据与人类对健康志愿者、阿尔茨海默氏症和2型糖尿病患者的研究表明，鼻腔胰岛素改善认知功能是一致的。这些初步发现有力地表明，直接注射到大脑的胰岛素可能会保护或恢复艾滋病毒感染者的神经功能。

 DESCRIPTION (provided by applicant): HIV-associated neurocognitive disorders (HAND) continue to be a remarkably prevalent condition in HIV- infected individuals despite the potent effects of combination antiretroviral therapy (cART). The development of HAND represents an important treatment issue for HIV patients that impacts quality of life, mortality, and everyday functioning. Currently, despite 25 years of research, no specific treatments have entered clinical practice for HAND. The overarching aim of this proposal is the development of a novel therapy, intranasal insulin, for HIV-associated neurocognitive disorders (HAND). We have identified this as an innovative, and high potential target based on our preliminary research. HIV-infection and cART are well known to cause alterations in lipid distribution, glucose homeostasis, and energy metabolism that are associated with alterations in insulin signaling. Several decades of research have shown that insulin has multiple actions in brain that regulate many of the same neural pathways perturbed by HIV infection including energy metabolism, lipid metabolism, neurotransmitter channel activity, neurite outgrowth, synaptic strength, and inflammatory signaling suggesting that insulin might protect the CNS in the setting of HIV-infection. In preliminary experiments we found that insulin protected neurons from a broad variety of insults including toxic HIV proteins, as well as ischemic, oxidative, inflammatory, and excitotoxic challenges, in addition to dampening the inflammatory response of microglia. In a novel animal model of HAND produced by infection of conventional mice with a chimeric HIV (EcoHIV) we found that intranasal insulin treatment for 9 days completely reversed cognitive impairment in infected animals. These data are consistent with human studies in healthy volunteers, Alzheimer's and type 2 diabetes patients showing that intranasal insulin improves cognitive function. These preliminary findings strongly suggest that insulin delivered directly to brain may preserve or restore neuronal function in HIV-infected individuals.