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

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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.