Evaluating Changes to the Metabolic Profile of the Central Nervous System due to Active NeuroHIV Infection

评估活动性 NeuroHIV 感染引起的中枢神经系统代谢特征的变化

• 批准号: 10365501
• 负责人: Cory Justin White
• 金额: $ 7.85万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10365501
• 关键词: Evaluating; Changes; Metabolic; Profile; Central

PROJECT SUMMARY/ABSTRACT Defects in lipid metabolism are associated with neurological diseases and mood disorders, but bioenergetics and regulation of lipid metabolism in the brain is not well defined. The brain is the most lipid-rich tissue in mammals other than adipose with a unique profile of lipids necessary for proper nervous system structure and function. However, how the brain uses lipids for energy and responds to dietary conditions that impact available lipids is grossly understudied. Historically, there has been little consideration for a) the existence, capacity, and relevance of fatty acid oxidation (FAO) in the brain in comparison to more prominent sources of energy such as glucose (and ketones during fasting and starvation) nor b) how the brain senses and adapts to changes in availability of lipids. Throughout my predoctoral training, I have already determined (Aim 1a) that the mammalian brain normally oxidizes long chain fatty acids in vivo to a greater extent than previously considered using a pan-brain-specific conditional mouse model incapable of FAO (manuscript in re- review in MCB) and (Aim 1b) identified that expression of ethanolamine phosphate phospholyase (Etnppl) (funded by F31, manuscript in prep), which has links to schizophrenia and bipolar disorder in humans, is upregulated by dietary fasting specifically in astrocytes from Ribo-Tag mice using translating ribosomal affinity purification. The contributions of ETNPPL to the brain metabolome were evaluated using constitutive ETNPPL knockout mice (ETNPPL-/-). Under the F99 phase, I will study (Aim 2a) how perturbations in hepatic FAO (supplies brain ketones), using mice with FAO deletion in both brain and liver, impacts FAO bioenergetics in brain and (Aim 2b) continue studying how the brain responds to metabolic cues by further characterizing ETNPPL in the brain using adeno-associated virus-injected ETNPPL overexpressed mice. In preparation for postdoctoral studies, I will expand my knowledge in neuro-HIV in a neuro-HIV seminar series, neuro-HIV course, and other didactic training opportunities offered at Johns Hopkins in the F99 phase. Aims 1 was and Aim 2 will be conducted in the laboratory of Michael Wolfgang, Ph.D. at Johns Hopkins School of Medicine during my graduate studies in the Biochemistry, Cellular and Molecular Biology Ph.D. Program. For the K00 phase, (Aim 3) I am pursuing postdoctoral training that will expand my current knowledge in lipid neurometabolism in the context of an infectious disease with neuropathological manifestations. I have a particular interest in the impact on brain lipid metabolism by HIV infection. This interest is based on high indices of cognitive impairment and dementia in HIV infected patients (collectively known as HAND), the brain being a reservoir for HIV, and antiretroviral drugs used long-term to treat HIV having metabolic side-effects. In summary, these training opportunities afforded by the support of the D-SPAN award would be immensely impactful towards my development into an innovative, independent researcher studying the intersection of neuroscience, metabolism, and infectious disease.

项目概要/摘要 脂质代谢缺陷与神经系统疾病和情绪障碍有关，但 大脑中脂质代谢的生物能量学和调节尚不明确。大脑是脂质最丰富的地方 除脂肪外的哺乳动物组织，具有正常神经系统所需的独特脂质特征 结构和功能。然而，大脑如何利用脂质获取能量并对饮食条件做出反应 对可用脂质的影响还没有充分研究。从历史上看，很少考虑 a) 与更突出的相比，大脑中脂肪酸氧化（FAO）的存在、能力和相关性 能量来源，如葡萄糖（以及禁食和饥饿期间的酮），也 b) 大脑如何感知 并适应脂质可用性的变化。在我的博士前训练中，我已经确定 （目标 1a）哺乳动物大脑通常在体内氧化长链脂肪酸的程度比 先前考虑使用无法进行FAO的泛脑特异性条件小鼠模型（手稿重新 MCB 中的审查）和（目标 1b）确定乙醇胺磷酸磷酸裂合酶 (Etnppl) 的表达 （由 F31 资助，手稿正在准备中）与人类精神分裂症和双相情感障碍有关，是 使用翻译核糖体亲和力通过禁食饮食上调，特别是在 Ribo-Tag 小鼠的星形胶质细胞中 纯化。使用组成型 ETNPPL 评估 ETNPPL 对脑代谢组的贡献 基因敲除小鼠（ETNPPL-/-）。在F99阶段，我将研究（目标2a）肝脏FAO中的扰动如何 （提供脑酮），使用脑部和肝脏均缺失FAO的小鼠，影响FAO生物能学 大脑和（目标 2b）通过进一步表征继续研究大脑如何响应代谢线索 使用腺相关病毒注射的 ETNPPL 过表达小鼠大脑中的 ETNPPL。准备中 博士后研究，我将在神经艾滋病毒研讨会系列中扩展我在神经艾滋病毒方面的知识，神经艾滋病毒 课程，以及约翰·霍普金斯大学在 F99 阶段提供的其他教学培训机会。目标 1 是并且 目标 2 将在 Michael Wolfgang 博士的实验室进行。在约翰霍普金斯大学医学院 在我攻读生物化学、细胞和分子生物学博士学位期间。程序。对于K00 阶段，（目标 3）我正在接受博士后培训，这将扩展我目前在脂质方面的知识 具有神经病理学表现的传染病背景下的神经代谢。我有一个 特别感兴趣的是艾滋病毒感染对脑脂质代谢的影响。这种兴趣是建立在高 HIV感染者的认知障碍和痴呆指数（统称为HAND）、大脑 是艾滋病毒的储存库，而长期用于治疗艾滋病毒的抗逆转录病毒药物会产生代谢副作用。在 总之，D-SPAN 奖项的支持提供的这些培训机会将是巨大的 对我发展成为一名创新的、独立的研究员研究交叉领域产生了影响 神经科学、新陈代谢和传染病。