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

项目摘要/摘要 脂代谢缺陷与神经系统疾病和情绪障碍有关，但 生物能量学和大脑中脂类代谢的调节还没有很好的定义。大脑中的脂质含量最高 哺乳动物中脂肪以外的组织，具有正常神经系统所必需的独特的脂类 结构和功能。然而，大脑如何利用脂类提供能量并对饮食条件做出反应 对可利用的脂类的影响研究严重不足。从历史上看，几乎没有考虑到a) 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(以及禁食和饥饿时的酮体)，以及b)大脑的感觉 并适应脂类可获得性的变化。在我的博士前训练中，我已经确定 (目标1a)哺乳动物大脑在体内正常氧化长链脂肪酸的程度大于 之前考虑使用一种泛脑特定的条件小鼠模型，不能与粮农组织合作(重新- Mcb)和(Aim 1b)中的综述证实乙醇胺磷酸解酶(Etnppl)的表达 (由F31资助，手稿在准备中)，与人类精神分裂症和双相情感障碍有关，是 利用翻译核糖体亲和力的Ribo-tag小鼠的星形胶质细胞通过饮食禁食特异性上调 净化。用构造性ETNPPL评价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)肝脏粮农组织的扰动是如何 (提供脑酮)，使用在大脑和肝脏中同时缺失FAO的小鼠，影响粮农组织的生物能量学 大脑和(目标2b)继续研究大脑如何对新陈代谢信号做出反应，通过进一步表征 ETNPPL在脑内用腺相关病毒注射的小鼠体内过表达。为…做准备 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。AIMS 1过去和现在 Aim 2将在约翰·霍普金斯大学医学院迈克尔·沃尔夫冈博士的实验室进行 在我攻读生物化学、细胞和分子生物学博士学位期间。对于K00 阶段，(目标3)我正在进行博士后培训，这将扩大我目前在脂质方面的知识 在具有神经病理表现的传染病的背景下的神经代谢。我有一个 对艾滋病毒感染对脑脂代谢的影响特别感兴趣。这种兴趣是建立在高额的 HIV感染患者(统称为手)认知障碍和痴呆的指标，脑 作为艾滋病毒的宿主，长期使用抗逆转录病毒药物治疗艾滋病毒会产生代谢副作用。在……里面 总而言之，在D-SPAN奖的支持下，这些培训机会将是巨大的 对我发展成为一名创新的独立研究员产生了影响，研究 神经科学、新陈代谢和传染病。

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.