This proposal will use a cell-specific and region-specific transcriptomics approach in the MS preclinical model to reveal new candidate targets for a tailored, disability-specific, neuroprotective treatment approach in MS. Neurological pathways underling walking, vision, and cognition differ, as do the cells and molecules within the neuroanatomic regions that serve them. MS patients are heterogeneous with regard to which disability is the most severely affected. Thus, we hypothesize that a one size fits all neuroprotective treatment for all disabilities in MS may not be possible. Rather, a disability specific discovery approach is needed.
Aim #1. Identify neurodegenerative mechanisms using the region-specific astrocyte transcriptome in EAE, here focusing beyond spinal cord, on optic nerve and hippocampus.
Aim #2. Identify neurodegenerative mechanisms using the region-specific neuronal transcriptome in EAE.
Aim #3. Use region-specific oligodendrocyte transcriptomics to determine molecular mechanisms of remyelination in two complementary MS models.
Aim #4. To begin to translate findings to MS, we will determine whether the alteration in gene expression in key pathways in MS models occurs in MS using human autopsy tissues. Together, this proposal will reveal distinct cell-specific and region-specific mechanisms underlying walking, vision, and cognitive disability in MS.
Multiple sclerosis is a leading cause of neurologic disability in young and middle aged adults. Disabilities vary markedly from patient to patient, and there are no disease modifying therapies to improve disabilities. Here we will address mechanisms underlying each distinct disability (walking, vision, cognition) to suggest novel candidates as disability specific neuroprotective treatments.
