'Intranasal Insulin Therapy for HIV- Associated Neurocognitive Disorders'

 描述（由申请人提供）：尽管联合抗逆转录病毒疗法（cART）具有强效作用，但HIV相关神经认知障碍（HAND）仍然是HIV感染个体中非常普遍的病症。HAND的发展代表了HIV患者的一个重要治疗问题，影响生活质量、死亡率和日常功能。目前，尽管有25年的研究，但尚未有具体的治疗方法进入HAND的临床实践。该提案的总体目标是开发一种新的治疗方法，鼻内胰岛素，用于HIV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会引起脂质分布、葡萄糖稳态和能量代谢的改变，这些改变与胰岛素信号传导的改变有关。几十年的研究表明，胰岛素在大脑中具有多种作用，调节许多受HIV感染干扰的相同神经通路，包括能量代谢、脂质代谢、神经递质通道活性、神经突生长、突触强度和炎症信号传导，这表明胰岛素可能在HIV感染的情况下保护CNS。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，还保护神经元免受各种各样的损伤，包括毒性HIV蛋白，以及缺血，氧化，炎症和兴奋性毒性挑战。在用嵌合HIV（EcoHIV）感染常规小鼠产生的HAND新动物模型中，我们发现鼻内胰岛素治疗9天完全逆转了感染动物的认知障碍。这些数据与在健康志愿者、阿尔茨海默病和2型糖尿病患者中进行的人体研究一致，表明鼻内胰岛素可改善认知功能。这些初步研究结果有力地表明，直接输送到大脑的胰岛素可以保护或恢复HIV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.