NutraStem as a neuroprotectant: Implications for neurogenesis in HAART treated patients

NutraStem 作为神经保护剂：对 HAART 治疗患者神经发生的影响

基本信息

批准号：
8923974
负责人：
Brian Giunta
金额：
$ 21.14万
依托单位：
NATURA THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8923974
关键词：
Accounting Address Adherence Adult Adverse effects Affect Age-Months Aging Atrophic Attenuated Autopsy Behavioral Blood Circulation Brain Cell Proliferation Cells Chronic Cognition Cognition Disorders Cognitive Cognitive deficits Detection Development Excision Foundations Functional Magnetic Resonance Imaging Future HIV HIV Infections HIV Seropositivity HIV tat Protein HIV-1 Highly Active Antiretroviral Therapy Hippocampus (Brain)Immunohistochemistry Impaired cognition Impairment In Vitro Individual Infection Control Lamivudine Lead Learning Mediating Mediator of activation protein Memory Messenger RNA Mind Mitochondria Mus Neurocognition Neurocognitive Neurocognitive Deficit Neurodegenerative Disorders Neurons Neuroprotective Agents Oxidative Stress Parahippocampal Gyrus Pathology Patients Peripheral Population Prevalence Prevention Process Production Reactive Oxygen Species Regimen Risk Factors Short-Term Memory Stress Task Performances Testing Transgenic Mice Transgenic Organisms Viral Viral Load result Virus Zidovudine base cell type dentate gyrus design efavirenz experience in vivo mouse model nerve stem cell neurocognitive test neurogenesis neuroprotection neurotoxic neurotoxicity non-nucleoside reverse transcriptase inhibitors novel object recognition prevent public health relevance relating to nervous system research study respiratory stem cell population tat Protein trend virtual

项目摘要

DESCRIPTION (provided by applicant): We designed an experiment to understand the interactions between loss of development of new neurons (neurogenesis) in the brain, HIV-1 Tat protein, and the known cognitive side-effects imparted by chronic highly active antiretroviral therapy (HAART). We preliminarily found the common HAART combination for HIV patients ,lamivudine/zidovudine/efavirenz (3TC/AZT/EFV): (1) reduced primary neural stem cell proliferation in vitro (2) increased NSC mitochondrial oxidative stress and that these could be opposed in vitro by NutraStem(r). We also show this regimen decreases hippocampal neurogenesis in vivo. We hypothesize NutraStem(r) will oppose HAART and Tat mediated neurogenesis pathology by reducing the effect of these two components on mitochondrial stress, in turn promoting neurogenesis, and reducing neurocognitive deficits in HIV-1 Tat transgenic mice. Here we plan to characterize neurocognition, and neurogenesis in HIV-1 Tat mice chronically treated with HAART. EFV or EFV/3TC/AZT should lead to advanced neurocognitive deficits in these mice that should be enhanced by brain HIV-1 Tat expression which that can be correlated with decreases in neurogenesis, compared to control AZT, or 3TC treated mice. NutraStem(r) should attenuate this phenomenon. We expect that other indicators of this NutraStem(r) mediated neuroprotection will include a reduction of memory problems which will be tested and brain mitochondrial stress in the Tat/HAART exposed mice. This study is expected to describe the long-term consequences of chronic Tat expression with use of a common HAART regimen plus a neuroprotectant (NutraStem(r)) in terms of neurogenesis and cognitive deficits. It should lay the foundation for effective strategies to prevent these interactions between Tat, HAART, and neurogenesis in the future in the context of a known HAART-mediated pathophysiological mechanism.

描述（由申请人提供）：我们设计了一项实验来了解大脑中新神经元（神经发生）发育丧失、HIV-1 Tat 蛋白以及慢性高活性抗逆转录病毒治疗带来的已知认知副作用之间的相互作用。我们初步发现HIV患者常用的HAART组合拉米夫定/齐多夫定/依非韦伦（3TC/AZT/EFV）：（1）减少初级神经干细胞。体外细胞增殖 (2) 增加 NSC 线粒体氧化应激，并且 NutraStem(r) 可以在体外抑制这些氧化应激。我们还发现，该方案会降低体内海马神经发生。我们发现 NutraStem(r) 会对抗 HAART 和 Tat 介导的神经发生。通过减少这两种成分对线粒体应激的影响，进而促进神经发生，并减少 HIV-1 Tat 转基因小鼠的神经认知缺陷，我们计划对神经认知进行表征。相比之下，长期接受 HAART 或 EFV/3TC/AZT 治疗的 HIV-1 Tat 小鼠的神经发生应导致这些小鼠出现严重的神经认知缺陷，这种缺陷应通过大脑 HIV-1 Tat 表达而增强，这可能与神经发生的减少相关。控制 AZT 或 3TC 治疗的小鼠应该会减弱这种现象，我们预计这种 NutraStem(r) 介导的神经保护作用的其他指标将包括减少将要测试的记忆问题以及 Tat/HAART 暴露小鼠的脑线粒体应激本研究预计将描述使用常见的 HAART 方案加神经保护剂 (NutraStem(r)) 时慢性 Tat 表达的长期后果。）在神经发生和认知缺陷方面，它应该为未来在已知的 HAART 介导的病理生理机制的背景下防止 Tat、HAART 和神经发生之间的相互作用奠定基础。