- PhD, University of Pierre and Marie Curie
- Associate Professor, Neuroscience
Exploring new therapeutics avenues to treat Multiple Sclerosis.
Multiple Sclerosis is a currently incurable autoimmune disease that affects 400,000 Americans and millions worldwide. The disease is characterized by destruction of myelin, the protective coat that wraps neuronal axons in the brain, thereby impairing the function of these “denuded” neurons. Depending on the position of the MS lesion(s) in the brain, the symptoms associated with the disease are very diverse and often debilitating. The main destructive force in MS is caused through the activation of T cells, which initiate myelin degradation and the development of autoimmunity. Although the etiology of MS is poorly understood, it is now clear that both genetic and environmental factors are involved.
The long-term goal of the laboratory is to discover novel therapeutic avenues for the treatment of Multiple Sclerosis. To achieve the ambitious goal of finding effective treatments for MS, it is critical to first unravel the mechanisms that drive disease pathology.
Project #1: Discovering new interventions that control the immune system during MS. Current immunomodulatory treatments for MS mostly act by blocking the migration of immune cells into the brain. While this strategy is protective, it comes with two major drawbacks; first, the immune-surveillance of the CNS is inhibited, opening the way for opportunistic infections, and second, these therapies are not effective against pathological immune cells that are already “on-site” in the brain. To bypass these pitfalls of first generation therapeutics, we are exploring cellular metabolic states and specific functions of the endoplasmic reticulum during the immunological response and pathology in MS.
Project #2: Promoting myelin repair to increase neuroprotection. Chronic demyelination is a major reason for disease progression and increased disability in MS patients, as exposed neurons become prone to neurodegeneration. Unfortunately, currently approved therapies are only aimed at dampening the immune response and do not address the critical need for stimulating myelin repair during/following an MS attack. Understanding the mechanisms of remyelination is critical in preventing neuronal loss, and is paramount to improving the quality of life of MS patients. We are using a combination of bioinformatics and animal studies to further our understanding of remyelination with the hope to develop new therapeutic options.
Project #3: Understanding the contribution of the gut microbiome to mental health. Major depressive disorder is the most common group of symptoms observed in MS patients (20%) and affects 5% of the total US population. Current therapies for depression are marred with severe side effects and incomplete efficacy. We have demonstrated that the gut microbiome is an active participant in initiation and progression of depression. In particular, we have demonstrated that Lactobacillus species of bacteria influence the host biology and control the production of pro-depressive compounds. We are currently further exploring the connection between the microbiome and mental health.
- Arandjelovic S, Perry J, Lucas C, Penberthy K, Kim T, Zhou M, Rosen D, Chuang T, Bettina A, Shankman L, Cohen A, Gaultier A, Conrads T, Kim M, Elliott M, Ravichandran K. A noncanonical role for the engulfment gene ELMO1 in neutrophils that promotes inflammatory arthritis. Nature immunology. 2019;20(2): 141-151. PMID: 30643265 | PMCID: PMC6402828
- Rosen D, Seki S, Fernández-Castañeda A, Beiter R, Eccles J, Woodfolk J, Gaultier A. Modulation of the sigma-1 receptor-IRE1 pathway is beneficial in preclinical models of inflammation and sepsis. Science translational medicine. 2019;11(478). PMID: 30728287
- Louveau A, Herz J, Alme M, Salvador A, Dong M, Viar K, Herod S, Knopp J, Setliff J, Lupi A, Da Mesquita S, Frost E, Gaultier A, Harris T, Cao R, Hu S, Lukens J, Smirnov I, Overall C, Oliver G, Kipnis J. CNS lymphatic drainage and neuroinflammation are regulated by meningeal lymphatic vasculature. Nature neuroscience. 2018;21(10): 1380-1391. PMID: 30224810 | PMCID: PMC6214619
- Norris G, Smirnov I, Filiano A, Shadowen H, Cody K, Thompson J, Harris T, Gaultier A, Overall C, Kipnis J. Neuronal integrity and complement control synaptic material clearance by microglia after CNS injury. The Journal of experimental medicine. 2018;215(7): 1789-1801. PMID: 29941548 | PMCID: PMC6028515
- Uchiyama R, Kupkova K, Shetty S, Linford A, Pray-Grant M, Wagar L, Davis M, Haque R, Gaultier A, Mayo M, Grant P, Petri W, Bekiranov S, Auble D. Histone H3 lysine 4 methylation signature associated with human undernutrition. Proceedings of the National Academy of Sciences of the United States of America. 2018;115(48): E11264-E11273. PMID: 30420518 | PMCID: PMC6275549
- Marin I, Goertz J, Ren T, Rich S, Onengut-Gumuscu S, Farber E, Wu M, Overall C, Kipnis J, Gaultier A. Microbiota alteration is associated with the development of stress-induced despair behavior. Scientific reports. 2017;7 43859. PMID: 28266612 | PMCID: PMC5339726
- Seki S, Gaultier A. Exploring Non-Metabolic Functions of Glycolytic Enzymes in Immunity. Frontiers in immunology. 2017;8 1549. PMID: 29213268 | PMCID: PMC5702622
- Seki S, Stevenson M, Rosen A, Arandjelovic S, Gemta L, Bullock T, Gaultier A. Lineage-Specific Metabolic Properties and Vulnerabilities of T Cells in the Demyelinating Central Nervous System. Journal of immunology (Baltimore, Md. : 1950). 2017;198(12): 4607-4617. PMID: 28507026 | PMCID: PMC5485845
- Chuang T, Guo Y, Seki S, Rosen A, Johanson D, Mandell J, Lucchinetti C, Gaultier A. LRP1 expression in microglia is protective during CNS autoimmunity. Acta neuropathologica communications. 2016;4(1): 68. PMID: 27400748 | PMCID: PMC4940960
- Fernandez-Castaneda A, Gaultier A. Adult oligodendrocyte progenitor cells - Multifaceted regulators of the CNS in health and disease. Brain, behavior, and immunity. 2016;57 1-7. PMID: 26796621 | PMCID: PMC4940337
- Walsh J, Hendrix S, Boato F, Smirnov I, Zheng J, Lukens J, Gadani S, Hechler D, Gölz G, Rosenberger K, Kammertöns T, Vogt J, Vogelaar C, Siffrin V, Radjavi A, Fernandez-Castaneda A, Gaultier A, Gold R, Kanneganti T, Nitsch R, Zipp F, Kipnis J. MHCII-independent CD4+ T cells protect injured CNS neurons via IL-4. The Journal of clinical investigation. 2015;125(6): 2547. PMID: 25938785
- Fernandez-Castaneda A, Arandjelovic S, Stiles T, Schlobach R, Mowen K, Gonias S, Gaultier A. Identification of the low density lipoprotein (LDL) receptor-related protein-1 interactome in central nervous system myelin suggests a role in the clearance of necrotic cell debris. The Journal of biological chemistry. 2012;288(7): 4538-48. PMID: 23264627 | PMCID: PMC3576060
- Stiles T, Dickendesher T, Gaultier A, Fernandez-Castaneda A, Mantuano E, Giger R, Gonias S. LDL receptor-related protein-1 is a sialic-acid-independent receptor for myelin-associated glycoprotein that functions in neurite outgrowth inhibition by MAG and CNS myelin. Journal of cell science. 2012;126 209-20. PMID: 23132925 | PMCID: PMC3603516