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Our Research

Dickey research neurodegeneration

Broadly, my current research is focused on determining how alterations in activity of a transcription factor can have wide-ranging downstream effects on multiple cellular pathways and other regulatory mechanisms (miRNAs) in healthy and disease states. I integrate Next-Gen sequencing, neuroscience, biochemistry, primary neurons, and preclinical trials with mouse models to generate and test novel therapeutic interventions in Huntington’s disease and Parkinson’s disease.  I am also fascinated by how mitochondria can affect the development of neurons, and their response to ‘insult’ whether stroke or disease.   I enjoy training and mentoring other scientists to undertake meaningful large-scale research projects and achieve high-quality results in a timely fashion.
 
With my background in signaling pathways, I strove to determine the mechanism underlying poly-Q-expanded huntingtin (pQhtt) interference in transcription downstream of PGC1a – without any direct interaction between pQhtt & PGC1a. I identified PPARd transcription dysregulation as the basis for HD mitochondrial dysfunction stemming from PGC-1a interference, and established that PPARd is an essential regulator in CNS. After seeing my results with a sub-optimal PPARd agonist, a collaborator approached, proposing a compound that had already progressed through human Phase 1B trials (diabetes), but was not commercially available. Based upon this discovery, I repurposed this potent, selective PPARd agonist (KD3010), and documented its utility as a treatment for HD in a preclinical trial in a HD mouse model and in medium spiny neurons derived from HD patient iPSCs. I also determined that as part of this signaling pathway, PPARd did not act alone, and found that activation of RXR, a transcription factor that heterodimerizes with PPARd (among others), is similarly capable of neuroprotection in HD. My team determined that PPARd neuroprotection stems from enhanced energy production and improved protein and mitochondrial quality control in the CNS.