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

基本信息

批准号：
10576395
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
项目类别：
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/10576395
关键词：
Address Adipose tissue Affinity Chromatography Anti-Retroviral Agents Astrocytes Autopsy Award Biochemistry and Cellular Biology Bioenergetics Biological Assay Bipolar Disorder Brain Carbohydrates Carnitine Palmitoyltransferase I Central Nervous System Cognition Communicable Diseases Cues Defect Dementia Dependovirus Development Diet Disease Doctor of Philosophy Drug usage Energy-Generating Resources Enzymes Epilepsy Fasting Fatty Acids Fatty acid glycerol esters Fellowship Funding Future Genes Genetic Genetic Transcription Glucose Goals HIV HIV Infections HIV-associated neurocognitive disorder Hepatic Homeostasis Human Impaired cognition Impairment Incidence Infection Intervention Ketone Bodies Ketones Knock-out Knockout Mice Knowledge Laboratories Link Lipids Liver Mammals Manuscripts Membrane Mental Depression Mentors Metabolic Metabolism Molecular Biology Mood Disorders Mus National Research Service Awards Nervous System Nervous System Physiology Neurologic Neurosciences Patients Peripheral Persons Phase Phosphatidylethanolamine Phospholipids Postdoctoral Fellow Predisposition Preparation Radiolabeled Regulation Research Research Personnel RiboTag Ribosomes Role Schizophrenia Series Source Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Starvation Structure Therapeutic Tissues Training Translating Work acylcarnitine antiretroviral therapy autism spectrum disorder brain metabolism career conditional knockout dietary experimental study fatty acid metabolism fatty acid oxidation in vivo indexing innovation interest ketogentic lipid metabolism long chain fatty acid mass spectrometric imaging medical schools metabolic profile metabolome metabolomics mouse model nervous system disorder neuroAIDS neuropathology overexpression oxidation phosphoethanolamine post-doctoral training pre-doctoral programs response side effect skill acquisition skills tool training opportunity

项目摘要

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.

项目摘要/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学和调节尚未很好地定义。大脑是脂肪最丰富的除脂肪以外的哺乳动物中的组织，具有适当神经系统所需的脂质独特的特征结构和功能。但是，大脑如何将脂质用于能量并应对饮食状况可用脂质的撞击已严格研究。从历史上看，几乎没有考虑a）与更突出的相比，大脑中脂肪酸氧化（FAO）的存在，能力和相关性葡萄糖（和禁食和饥饿期间的酮）等能源的来源也不并适应脂质的可用性变化。在我的整个培训期间，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以前考虑过使用无粮农组织的泛脑特异性小鼠模型（手稿在MCB中的综述）和（AIM 1B）确定乙醇胺磷酸磷酸酶（ETNPPL）的表达（由F31资助，PREP中的手稿），与人类的精神分裂症和双相情感障碍有联系使用翻译核糖体亲和力的饮食禁食专门在核糖小鼠的星形胶质细胞中上调纯化。使用构型ETNPPL评估ETNPPL对脑代谢组的贡献敲除小鼠（etnppl - / - ）。在F99阶段，我将研究（AIM 2A）肝粮农组织的扰动（提供脑酮），使用大脑和肝脏中的粮农组织缺失的小鼠会影响粮农组织的生物能力大脑和（AIM 2B）继续研究大脑如何通过进一步表征来对代谢线索的反应使用腺相关的病毒ETNPPL过表达的小鼠，大脑中的ETNPPL。准备博士后研究，我将在神经HIV研讨会系列中扩展我对神经hiv的知识在F99阶段，约翰·霍普金斯（Johns Hopkins）提供的课程以及其他教学培训机会。目标1是 AIM 2将在Michael Wolfgang博士的实验室进行。在约翰·霍普金斯医学院在我从事生物化学的研究生研究期间，细胞和分子生物学博士学位。程序。对于K00 阶段，（目标3）我正在进行博士后培训，以扩大我目前的脂质知识神经代谢在具有神经病理学表现的传染病的背景下。我有一个 HIV感染对对脑脂质代谢的影响特别感兴趣。这种兴趣基于高艾滋病毒感染患者的认知障碍和痴呆症指数（统称为手），大脑作为HIV的储库，抗逆转录病毒药物长期用于治疗具有代谢副作用的HIV。在总而言之，由D-SPAN奖的支持提供的这些培训机会将是极大的对我发展成为创新的独立研究人员的影响力的影响神经科学，代谢和传染病。