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:
  • 金额:
    $ 7.85万
  • 依托单位:
  • 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

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.
项目总结/摘要 脂质代谢缺陷与神经系统疾病和情绪障碍有关, 生物能量学和脑中脂质代谢的调节还没有很好地定义。大脑是最富含脂质的 哺乳动物中脂肪以外的组织,具有适当神经系统所需的独特脂质分布 结构和功能。然而,大脑如何利用脂质作为能量,以及如何对饮食条件做出反应, 影响可用脂质是严重不足的研究。从历史上看,很少考虑a) 脂肪酸氧化(FAO)在大脑中的存在,能力和相关性相比, 能量来源,如葡萄糖(和酮在禁食和饥饿)也没有B)大脑如何感觉 并适应脂质可用性的变化。在我的博士前培训中,我已经确定 (Aim 1a)哺乳动物大脑通常在体内氧化长链脂肪酸的程度大于 先前考虑使用不能FAO的泛脑特异性条件小鼠模型(手稿在re-brain-specific conditional mouse model), MCB中的综述)和(目的1b)确定了乙醇胺磷酸磷脂酶(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, 使用翻译核糖体亲和力在Ribo-Tag小鼠的星形胶质细胞中特异性地通过饮食禁食上调 洁净.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中的扰动如何影响 (提供脑酮),使用大脑和肝脏中FAO缺失的小鼠, 大脑和(目标2b)继续研究大脑如何响应代谢线索,进一步表征 使用腺相关病毒注射的ETNPPL过表达小鼠的脑中的ETNPPL。为筹备 博士后研究,我将扩大我的知识,在神经艾滋病毒的神经艾滋病毒研讨会系列,神经艾滋病毒 课程,和其他教学培训机会提供约翰霍普金斯在F99阶段。目标1是和 目标2将在Michael Wolfgang博士的实验室进行。在约翰霍普金斯医学院 在我的研究生学习期间,在生物化学,细胞和分子生物学博士学位。程序.对于K 00 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 在具有神经病理学表现的感染性疾病的背景下,神经代谢。我有一个 特别感兴趣的是HIV感染对脑脂质代谢的影响。这种兴趣是基于高 HIV感染患者的认知障碍和痴呆指数(统称为HAND), 作为HIV的储存库,长期用于治疗HIV的抗逆转录病毒药物具有代谢副作用。在 总而言之,D-SPAN奖的支持所提供的这些培训机会将极大地 对我的发展有影响,成为一个创新的,独立的研究人员,研究的交叉点, 神经科学、新陈代谢和传染病。

项目成果

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Cory Justin White其他文献

Cory Justin White的其他文献

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{{ truncateString('Cory Justin White', 18)}}的其他基金

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
  • 财政年份:
    2020
  • 资助金额:
    $ 7.85万
  • 项目类别:
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:
    10398990
  • 财政年份:
    2020
  • 资助金额:
    $ 7.85万
  • 项目类别:

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