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Research Summary

Currently available immunomodulatory therapies for multiple sclerosis (MS) fail to ameliorate the pathogenesis of established axon degeneration and are only partially effective in preventing the onset of permanent disability. Identifying a drug that stimulates endogenous remyelination and spares axon degeneration would theoretically reduce the rate of, or even halt, disease progression. The Tiwari-Woodruff lab investigates mechanisms of demyelination-induced neurodegeneration and therapeutic neuroprotection using two demyelinating mouse models of MS: immune-mediated experimental autoimmune encephalomyelitis (EAE) and non-immune-mediated toxic cuprizone diet. Additionally, through continued collaborations with researchers at UIUC, UCLA, and pharmaceutical companies, the lab interrogates therapeutic efficacies and mechanisms of action of various approved and potential MS drugs. Our research is divided into the following five projects:

• CNS pathology and translational biomarkers: A major focus is on the timing and extent of inflammation, demyelination, and axon degeneration in experimentally-induced demyelinating/remyelinating CNS. We aim to identify translational biomarkers for drug discovery and treatment optimization in mice and men. To this end, we use longitudinal imaging (e.g., diffusion tensor imaging, DTI, and optical coherence tomography, OCT), electrophysiological (e.g., visual evoked potential, VEP) endpoints, and serum biomarkers (e.g., growth factors, pro- and anti-inflammatory cytokines) within rodent models of MS that can be directly translated to use in humans.​
• Cognition and disease: Cognitive processes include attention, memory, learning, organizing, comprehending, thinking, and judgement. As a result of inflammatory demyelination and neurodegeneration wihin the brain, approximately 50% of MS patients develop cognitive deficits. We aim to characterize cognitive dysfunction and identify affected brain regions in mouse models of chronic MS through behavioral assays, electrophysiological recordings, and pathology. Our goal is to alleviate these profoundly quality-of-life diminishing cognitive dysfunctions using optimized therapeutics.​​
• Use of estrogen receptor β ligands to stimulate functional axon remyelination: The Tiwari-Woodruff lab examines the role of estrogen and estrogen receptor (ER) β ligands as neuroprotective agents. We have been actively identifying the most specific and efficacious therapeutic ER β ligands so that they may be quickly moved from bench-to-bedside for MS therapy. Additionally, we acquire novel and published ER β ligands from academic collaborators and private companies in the hopes that a functionally-relevant remyelinating, neuroprotective therapy might reach MS patients in the near future.​​
• Role of sex hormones and sex chromosomes in myelination during development and disease: Many diseases exhibit gender biased incidence, with males and females differing in the age at onset and disease severity. MS, for example, has a 4:1 female to male occurrence. On the other hand, pervasive neurodevelopmental disorders such as autism/Asperger and Tourette syndrome affect more males than females. While sex differences in immune responses are well-characterized, less is known about sex differences in myelination. We recently showed that remyelination is more efficient in females regardless of whether circulating sex hormones are present or absent. In addition, a clear sex chromosome complement difference (in the absence of circulating sex hormones) is observed during remyelination. Using four core genotype mice our recent study revealed that XX (males and females) animals achieve superior levels of recovery from demyelination compared to sex-matched XY animals. Importantly, these data inform studies of the organizing and activating effects of sex chromosomes on oligodendrocytes and myelination. Presently, we are investigating genes that may influence myelination during development and/or repair.​
• Histopathology of human MS in postmortem tissue: Regionally-selective brain atrophy is detectable early in the course of MS and is associated with verbal memory impairments. In vivo imaging offers insight into early MS disease effects, but lacks specificity. Histochemical probing of postmortem brain tissue samples provides detailed insight into pathology. Regional distribution of surviving and apoptotic oligodendrocytes, extent of demyelination, characterization of inflammation at sites of demyelination, and disease stage are being investigated using MS postmortem tissue.

*Dr. Tiwari-Woodruff’s research program is funded by grants from the NIH, the NMSS, and from various pharmaceutical companies.