OUR PROJECTS
01
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.
02
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.
03
Use of estrogen receptor 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.
04
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.
05
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.
MEET THE LAB
Seema Tiwari-Woodruff, Ph.D.
Professor, Biomedical Sciences
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B.S., Biology, Biology, Government Science College, Jabalpur, India
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M.S., Chemistry, Southern Illinois University, Carbondale, IL
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Ph.D., Physiology, Southern Illinois University, Carbondale, IL
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Postdoctoral Fellow, Department of Physiology/Neurology, School of Medicine, UCLA
Email:
PUBLICATIONS
Sekyi, Maria & Lauderdale, Kelli & Atkinson, Kelley & Golestany, Batis & Karim, Hawra & Feri, Micah & Soto, Joselyn & Diaz, Cobi & Kim, Sung & Cilluffo, Marianne & Nusinowitz, Steven & Katzenellenbogen, John & Tiwari-Woodruff, Seema. (2020). Alleviation of extensive visual pathway dysfunction by a remyelinating drug in a chronic mouse model of multiple sclerosis. Brain Pathology. 31. 10.1111/bpa.12930.
Diffusion tensor imaging identifies aspects of therapeutic estrogen receptor β ligand-induced remyelination in a mouse model of multiple sclerosis. Atkinson KC, Lee JB, Hasselmann JPC, Kim SH, Drew A, Soto J, Katzenellenbogen JA, Harris NG, Obenaus A, Tiwari-Woodruff SK. 2019 Neurobiol Dis.130:104501. doi: 10.1016/j.nbd.2019.104501. [Epub ahead of print]
Didonna A, Cantó E, Shams H, Isobe N, Zhao C, Caillier SJ, Condello C, Yamate-Morgan H, Tiwari-Woodruff SK, Mofrad MRK, Hauser SL, Oksenberg JR. Sex-specific Tau methylation patterns and synaptic transcriptional alterations are associated with neural vulnerability during chronic neuroinflammation. J Autoimmun. 2019 Apr 19. pii: S0896-8411(19)30019-8. Do: 10.1016/j. gut. 2019.04.003.
Yamate-Morgan H, Lauderdale K, Horeczko J, Merchant, U, Tiwari-Woodruff SK. Functional Effects of Cuprizone-Induced Demyelination in the Presence of the mTOR-Inhibitor Rapamycin. Neuroscience. 2019 Jan 29. pii: S0306-4522(19)30058-2. doi: 10.1016/j.neuroscience.2019.01.038
Karim H, Kim SH, Lauderdale K, Lapato AS, Atkinson K, Yasui N, Yamate-Morgan H, Sekyi M, Katzenellenbogen JA, Tiwari-Woodruff SK. Analogues of ERβ ligand chloroindazole exert immunomodulatory and remyelinating effects in a mouse model of multiple sclerosis. Sci Rep. 2019 Jan 24;9(1):503. doi: 10.1038/s41598-018-37420-x.
Karim H, Kim SH, Lapato AS, Yasui N, Katzenellenbogen JA, Tiwari-Woodruff SK. Increase in chemokine CXCL1 by ERβ ligand treatment is a key mediator in promoting axon myelination (24): 6291-6296. Proc Natl Acad Sci U S A. 2018 Jun 12; 115
Lapato AS, Szu J, Hasselmann JP, Khalaj AJ, Binder DK, Tiwari-Woodruff SK. (2017). Chronic demyelination-induced seizures. Neuroscience
Hasselmann JP, Karim H, Khalaj AJ, Ghosh S, Tiwari-Woodruff SK. (2017) Consistent induction of chronic experimental autoimmune encephalomyelitis in C57BL/6 mice for the longitudinal study of pathology and repair. J Neurosci Methods. 2017 Jun 1;284:71-84
Khalaj AJ, Hasselmann J, Augello C, Moore S, Tiwari-Woodruff SK. (2016). Nudging oligodendrocyte intrinsic signaling to remyelinate and repair: Estrogen receptor ligand effects. J Steroid Biochem Mol Biol 160:43-56.
Moore SM, Khalaj AJ, Kumar S, Winchester Z, Yoon J, Yoo T, Martinez-Torres L, Yasui N, Katzenellenbogen JA, Tiwari-Woodruff SK. Multiple functional therapeutic effects of the estrogen receptor β agonist indazole-Cl in a mouse model of multiple sclerosis. 2014. Proc Natl Acad Sci U S A. Dec 16;111(50):18061-6.
Khalaj AJ, Yoon J, Nakai, J, Winchester Z, Moore SM, Yoo T, Martinez-Torres L, Kumar S, Itoh N, Tiwari-Woodruff SK: Estrogen receptor (ER) beta expression in oligodendrocytes is required for attenuation of clinical disease by an ERbeta ligand. P Natl Acad Sci USA 2013.
Patel R, Moore S, Crawford DK, Hannsun G, Sasidhar MV, Tan K, Molaie D, Tiwari-Woodruff SK: Attenuation of corpus callosum axon myelination and remyelination in the absence of circulating sex hormones. Brain pathology 2013, 23(4):462-475.
Moore, S, Patel R, Hannsun G, Yang J, Tiwari-Woodruff SK: Sex chromosome complement influences functional callosal myelination. Neuroscience 2013, 245:166-178.
Moore, S, Khalaj AJ, Yoon J, Patel R, Hannsun G, Yoo T, Sasidhar M, Martinez-Torres L, Hayardeny L, Tiwari-Woodruff SK: Therapeutic laquinimod treatment decreases inflammation, initiates axon remyelination, and improves motor deficit in a mouse model of multiple sclerosis. Brain and behavior 2013, 3(6):664-682.
Kumar S, Patel R, Moore S, Crawford DK, Suwanna N, Mangiardi M, Tiwari-Woodruff SK: Estrogen receptor beta ligand therapy activates PI3K/Akt/mTOR signaling in oligodendrocytes and promotes remyelination in a mouse model of multiple sclerosis. Neurobiology of disease 2013, 56:131-144.
Bankston AN, Li W, Zhang H, Ku L, Liu G, Papa F, Zhao L, Bibb JA, Cambi F, Tiwari-Woodruff SK, et al: P39, the Primary Activator for Cyclin-dependent Kinase 5 (Cdk5) in Oligodendroglia, Is Essential for Oligodendroglia Differentiation and Myelin Repair. The Journal of biological chemistry 2013, 288(25):18047-57
Mangiardi M, Crawford DK, Xia X, Du S, Simon-Freeman R, Voskuhl RR, Tiwari-Woodruff SK: An animal model of cortical and callosal pathology in multiple sclerosis. Brain pathology 2011, 21(3):263-278.
Crawford DK, Mangiardi M, Song B, Patel R, Du S, Sofroniew MV, Voskuhl RR, Tiwari-Woodruff SK: Oestrogen receptor {beta} ligand: a novel treatment to enhance endogenous functional remyelination. Brain 2010, 133(10):2999-3016.
Zen MO, Avedisian AA, Tiwari-Woodruff, S, Voskuhl RR: Hippocampal CA1 atrophy and synaptic loss during experimental autoimmune encephalomyelitis, EAE. Lab Invest 2010, 90(5):774-786.
Tiwari-Woodruff, S, Voskuhl RR: Neuroprotective and anti-inflammatory effects of estrogen receptor ligand treatment in mice. J Neurol Sci 2009, 286(1-2):81-85.
Crawford DK, Mangiardi M, Xia X, Lopez-Valdes HE, Tiwari-Woodruff SK: Functional recovery of callosal axons following demyelination: a critical window. Neuroscience 2009, 164(4):1407-1421.
Crawford DK, Mangiardi M, Tiwari-Woodruff SK: Assaying the functional effects of demyelination and remyelination: revisiting field potential recordings. J Neurosci Methods 2009, 182(1):25-33.
Tiwari-Woodruff, S, Morales LB, Lee R, Voskuhl RR: Differential neuroprotective and antiinflammatory effects of estrogen receptor (ER)alpha and ERbeta ligand treatment. Proc Natl Acad Sci U S A 2007, 104(37):14813-14818.
Tiwari-Woodruff, S, Beltran-Parrazal L, Charles A, Keck T, Vu T, Bronstein J: K+ channel KV3.1 associates with OSP/claudin-11 and regulates oligodendrocyte development. Am J Physiol Cell Physiol 2006, 291(4):C687-698.
Tiwari-Woodruff SK, Buznikov AG, Vu TQ, Micevych PE, Chen K, Kornblum HI, Bronstein JM: OSP/claudin-11 forms a complex with a novel member of the tetraspanin super family and beta1 integrin and regulates proliferation and migration of oligodendrocytes. J Cell Biol 2001, 153(2):295-305.
Tiwari-Woodruff SK, Lin MA, Schulteis CT, Papazian DM: Voltage-dependent structural interactions in the Shaker K(+) channel. J Gen Physiol 2000, 115(123-138.:2)