Investigating the Role of TDP-43 Pathology in TBI-induced Synaptic Mitochondria Bioenergetics and Neuronal Susceptibility: Implications for TBI Targeted Therapeutic Strategies

Grants and Contracts Details

Description

TDP-43 pathology is a key neuropathological hallmark in a spectrum of neurodegenerative disorders (Huang W (2020) including Traumatic Brain Injury (TBI) (Blennow K,(2012). The lack of disease-modifying agents against TDP-43 pathology particularly in TBI creates an urgent need to identify novel pathways and therapeutic agent for the TBI secondary molecular sequalae. Our unpublished and feasibility data finds that controlled cortical impact (CCI) aberrantly induces both TDP-43 mislocalization and eIF5AHyp in particularly vulnerable cortical and limbic-hypothalamic neuronal population. Our central hypothesis states that TBI-induced TDP-43 neuropathology activates eIF5AHyp pathwayand reducing hypusine levels will restore synaptic mitochondrial function and ameliorate TDP-43neuropathogenesis. In Aim 1, we will establish how mild and severe CCI impacts spatial-temporal profile of TDP-43 pathology in adult forebrain of the TDP-43 transgenic mice. We will establish acute and chronic eIF5AHyp and neuroinflammatory signatures, neurodegeneration, followed by behavior testing. In Aim 2, we will perform fractionated mitochondrial magnetic separation technique (FMMS) to measure synaptic mitochondrial bioenergetics. We will assess mitochondrial integrity and TDP-43/ eIF5AHyp accumulation via biochemical and imaging analysis. We will measure brain metabolic landscape, over 300+ metabolites, via targeted metabolomics and single quadrupole gas chromatography (GCMS/ QqQ) and ex vivo intra-organellar 13C3- pyruvate stable isotope-resolved metabolomics (SIRM) analysis. In Aim 3, we will perform a 14-day intraperitoneal (IP) GC7 administration in CCI mice and measure the efficacy of this strategy on neurometabolic dysfunction,TDP-43 pathology and behavior outcomes using biochemical and histological assays. We will measure treatment effects on TDP-43 synaptic mitochondrial accumulation and bioenergetics. Overall, this proposal will address this significant gap in knowledge by studying the impact of the eIF5A hypusination pathway (eIF5AHyp ) on the brain’s TDP-43 neuropathological changes and metabolic state in acute and chronic CCI mouse model.
StatusActive
Effective start/end date2/1/251/31/28

Funding

  • KY Spinal Cord and Head Injury Research Trust: $100,000.00

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