Transnasal Delivery of Chemokine Analogs in mouse NeuroAIDS Models

描述（由申请人提供）：HIV（人类免疫缺陷病毒）阳性个体的数量近年来有所上升，主要是因为联合抗逆转录病毒治疗（cART）帮助这些患者延长了寿命。然而，hiv相关神经认知障碍（HAND）的患病率也有所上升，因为cART药物通常不能有效地穿过血脑屏障。为了解决这一问题，我们建议评估一种针对HAND的新型治疗方法。在HAND患者和疾病过程的动物模型中，我们和其他人已经积累了神经元受损的证据。此外，来自我们实验室和其他实验室的新证据表明，神经aids患者大脑中的成体神经祖细胞（aNPCs）也减少了。活跃的神经发生通常发生在海马的齿状回。新生成的神经元被纳入神经网络，促进某些类型的学习和记忆。有趣的是，除了HAND外，海马神经发生在几种神经退行性疾病中也显着改变。最近，我们报道了与HAND发病机制相关的HIV包膜糖蛋白gp120在体外和体内抑制了神经艾滋病啮齿动物模型（HIV/gp120-转基因小鼠）海马齿状回中成体神经祖细胞的增殖。作为潜在的治疗方法，我们和我们的合作者已经合成了新的趋化因子受体（CXCR4和CCR5，它们是HIV/gp120的共受体）的肽抑制剂，并发现这些新的合成和模块化修饰（SMM）趋化因子在体外阻断gp120对神经祖细胞增殖的抑制作用。在这里，我们建议研究smm趋化因子在体内的有效性，从新的，非常选择性和无毒的CXCR4拮抗剂开始。特别是，我们建议研究经鼻（也称为鼻内）应用smm趋化因子是否可以防止神经艾滋病小鼠模型中成年神经祖细胞增殖的减少。值得注意的是，我们最近的研究表明，经鼻给药的多肽优先被输送到大脑，其他多肽已被FDA批准以这种方式在人类中用于大脑输送。我们提出了以下具体目的：(1)研究经鼻应用smm趋化因子类似物是否能保护HIV/gp120转基因小鼠的成年神经元并恢复成年海马祖细胞的增殖。值得注意的是，在未来的工作中，我们计划通过研究smm趋化因子类似物的经鼻应用是否也能保护神经元并恢复成年海马祖细胞的增殖，从而测试smm趋化因子类似物的“泛化”效应，在第二个神经艾滋病模型中，由NOD/scid-IL- 2rgnull小鼠组成，这些小鼠用人造血CD34+干细胞重组，然后感染HIV-1。这个模型是由我们的合作者Howard Gendelman博士和他的同事开发的，虽然更难以使用，但它非常接近地模拟了人类手部的进展和认知功能障碍。

DESCRIPTION (provided by applicant): The number of HIV (human immunodeficiency virus)-positive individuals has risen over recent years mainly because combination antiretroviral therapy (cART) is helping these patients live longer. However, the prevalence of HIV-Associated Neurocognitive Disorders (HAND) has also risen since cART drugs in general do not effectively cross the blood-brain-barrier. To address this issue, we propose to evaluate a new type of treatment targeted for HAND. In patients with HAND and in animal models of the disease process, we and others have accumulated evidence that neurons are damaged. Additionally, emerging evidence from our laboratory and others suggests that adult neuroprogenitor cells (aNPCs) are also decreased in the brains of patients with NeuroAIDs. Active neurogenesis normally occurs throughout life in the dentate gyrus in the hippocampus. Newly generated neurons are incorporated into the neural network, contributing to certain types of learning and memory. Intriguingly, hippocampal neurogenesis is significantly altered in several neurodegenerative diseases in addition to HAND. Recently, we reported that the HIV-envelope glycoprotein gp120, which is associated with HAND pathogenesis, inhibits proliferation of adult neural progenitor cells in vitro and in vivo in the dentate gyrus of the hippocampus in a NeuroAIDS rodent model, the HIV/gp120- transgenic mouse. As potential treatment, we and our collaborators have synthesized new peptide inhibitors of chemokine receptors (CXCR4 and CCR5, which are co-receptors for HIV/gp120), and found that these novel synthetically and modularly modified (SMM)-chemokines block the inhibitory effect of gp120 on neural progenitor proliferation in vitro. Here, we propose to investigate the effectiveness of SMM-chemokines in vivo, beginning with new, very selective and non-toxic CXCR4 antagonists. In particular, we propose to investigate whether transnasal (also called intranasal) application of SMM-chemokines can prevent the decrease in proliferation of adult neural progenitors in mouse models of NeuroAIDS. Notably, we have recently shown that transnasally administered-peptides are preferentially delivered to the brain, and other peptides have been approved in humans by the FDA for brain delivery in this fashion. We list the following Specific Aim: (1) To investigate whether transnasal application of SMM-chemokine analogs protects adult neurons and restores the proliferation of adult hippocampal progenitors in HIV/gp120-transgenic mice. Note that in future work, we plan to test for 'generalization' of the effect of the SMM-chemokine analogs by investigating whether transnasal application of SMM-chemokine analogs also protects neurons and restores the proliferation of adult hippocampal progenitors in a second NeuroAIDS model, consisting of NOD/scid-IL- 2Rgcnull mice that are reconstituted with human hematopoietic CD34+ stem cells and then infected with HIV-1. This model, as developed by our collaborator Dr. Howard Gendelman and colleagues, while more difficult to utilize, closely mimics human HAND progression and cognitive dysfunction.