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 Our unpublished and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.
Status | Active |
---|---|
Effective start/end date | 2/1/25 → 1/31/28 |
Funding
- KY Spinal Cord and Head Injury Research Trust: $100,000.00
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