Roberta Brambilla, Ph.D.
Associate Professor, Department of Neurological Surgery
Neuroinflammation and neuro-immune interactions in neurological disease
The main focus of my research is understanding the role of neuroinflammation in the pathophysiology of neurological disorders (e.g., multiple sclerosis, spinal cord injury, stroke), with a specific interest in the contribution of glial cells. We investigate astrocytes and microglia for their involvement in the neuroinflammatory response to injury, and oligodendrocytes and oligodendrocyte precursor cells for their role in axon myelination, metabolic support of neurons and myelin repair. We are also interested in the interaction between the immune system and the central nervous system (CNS), and how innate and adaptive immune responses driven by macrophages, T cells and B cells infiltrating into the CNS during disease influence neurological outcomes. Currently, our primary lines of research are centered on:
1) Understanding how tumor necrosis factor (TNF), both membrane-bound (tmTNF) and soluble (solTNF), as well as its receptors TNFR1 and TNFR2 participate in the processes of demyelination/remyelination and neuroinflammation. We demonstrated that tmTNF has a protective function in experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS), and this effect is mediated by the activation of TNFR2 in glial cells (Brambilla et al., Brain 2011; Madsen et al., J Neurosci, 2016; Gao et al., Cell Rep, 2017). This work supports the idea that TNFR2 can be exploited as a target for therapy, not only in MS but in other neurological disorders associated with inflammation and myelin damage. On this basis, our current work aims at: a) addressing the molecular mechanisms of TNFR2 protective functions in the CNS in various models of injury and disease (MS, spinal cord injury, traumatic brain injury, stroke); b) identifying selective TNFR2 agonists for the therapy of neurological disease.
2) Investigating whether mitochondrial dysfunction in oligodendrocytes plays a role in the pathophysiology of MS. Despite the general consensus on the autoimmune component of MS, its etiology remains unknown. An emerging view is that, at least in some forms of MS, a primary dysfunction within the CNS might be the initial trigger of the disease, then followed by the destructive autoimmune response. Our hypothesis is that mitochondrial dysfunction in oligodendrocytes is one of the causes of oligodendrocyte cell death and demyelination, leading to disease initiation. To investigate this hypothesis we use a transgenic mouse model generated in our lab where mitochondrial DNA (mtDNA) depletion can be timely and reversibly induced in myelinating oligodendrocytes (PLP:mtPstI mice, Madsen et al., 2017), leading to oligodendrocyte cell death and an MS-like phenotype. We are also addressing oligodendroglial mitochondrial function/dysfunction in CNS tissues from primary progressive MS patients with various approaches.
Roberta Brambilla, Ph.D.
- The Miami Project to Cure Paralysis
1095 NW 14th Terrace (R-48)
Miami, FL 33136
- (305) 243-7131
- (305) 243-3914
Society for Neuroscience
International Society for Neuroimmunology
Yli-Karjanmaa M. Larsen K.L., Fenger C.D., Kellemann Kristensen L., Martin N.A., Jensen P.T., Breton A., Nathanson L., Nielsen P.V., Christiansen Lund M., Lindeman Carlsen S., Gramsbergen J.B., Finsen B., Stubbe J., Frich L.H., Stolp H., Brambilla R., Anthony D.C., Meyer M., Lambertsen K.L. (2019) TNF deficiency causes alterations in the spatial organization of neurogenic zones and alters the number of microglia and neurons in the cerebral cortex. Brain Behavior Immunity, S0889-1591(19)30576-8.
Brambilla R*. (2019) The contribution of astrocytes to the neuroinflammatory response in multiple sclerosis and experimental autoimmune encephalomyelitis. Acta Neuropathol, 137:689-691.
Madsen P.M., Pinto M., Patel S., McCarthy S., Gao H., Taherian M., Karmally S., Pereira C.V., Dvoriantchikova G., Ivanov D., Tanaka K.F., Moraes C.T., Brambilla R.* (2017) Mitochondrial DNA double-strand breaks in oligodendrocytes cause demyelination, axonal injury and CNS inflammation. J Neurosci. 37:10185-10199.
Al-Ali H., Gao H., Dalby-Hansen C., Peters V.A., Shi Y., Brambilla R.* (2017) High content analysis of phagocytic activity and cell morphology with PuntoMorph. J. Neurosci. Methods 291:43-50.
Gao H., Danzi M.C., Choi C.S., Taherian M., Dalby-Hansen C., Ellman D.G., Madsen P.M., Bixby J.L., Lemmon V.P., Lambertsen K.L., Brambilla R.* (2017) Opposing functions of microglial and macrophagic TNFR2 in the pathogenesis of experimental autoimmune encephalomyelitis. Cell Rep. 18:198:212.
Clausen B.H., Degn M., Sivasaravanaparan M., Fogtmann T., Gammelstrup Andersen M., Trojanowsky M.D., Gao H., Hvidsten S., Baun C., Deierborg T., Finsen B., Kristensen B.W., Thornby Bak S., Meyer M., Lee J.K., Nedospasov S.A., Brambilla R., Lambertsen K.L. (2016) Conditional ablation of myeloid TNF increases lesion volume after experimental stroke in mice, possibly via altered ERK1/2 signaling. Sci. Rep. 6:29291.
Madsen P.M., Motti D., Karmally S., Szymkowski D.E., Lambertsen K.L., Bethea J.R., Brambilla R.* (2016) Oligodendroglial TNFR2 mediates membrane TNF-dependent repair in experimental autoimmune encephalomyelitis by promoting oligodendrocyte differentiation and remyelination. J. Neurosci. 36:5128-43.
Madsen P.M., Clausen B.H., Degn M., Thyssen S., Kellemann Kristensen L., Svensson M., Ditzel N., Finsen B., Deierborg T., Brambilla R.*, Lambertsen K.L. (2016) Genetic ablation of soluble TNF with preservation of membrane TNF is associated with neuroprotection after focal cerebral ischemia. J. Cereb. Blood Flow Metab. 36:1553-69.
Dellarole A., Morton P.D., Brambilla R., Walters W., Summers S., Bernardes D., Grilli M., and Bethea J.R. (2014) Neuropathic pain-induced depressive-like behavior and hippocampal neurogenesis and plasticity are dependent on TNFR1 signaling. Brain Behav. Immun. 41:65-81.
Brambilla R.*, Morton P.D., Ashbaugh J.J., Karmally S., Lambertsen K., and Bethea J.R. (2014) Astrocytes play a key role in EAE pathophysiology by orchestrating in the CNS the inflammatory response of resident and peripheral immune cells and by suppressing remyelination. GLIA 62:452-457.
Jopek Ashbaugh J., Brambilla R., Karmally S.A., Cabello C., Malek T.R., and Bethea J.R. (2013) IL7Rα contributes to EAE through altered T cell responses and non-hematopoietic cell lineages. J. Immunol. 190:4525-34.
Brambilla R.*, Dvoriantchikova G., Barakat D., Ivanov D., Bethea J.R., and Shestopalov V.I. (2012) Transgenic inhibition of astroglial NF-kB protects from optic nerve damage and retinal ganglion cell loss in experimental optic neuritis. J. Neuroinflamm. 9:213.
Brambilla R.*, Jopek Ashbaugh J., Magliozzi R., Dellarole A., Karmally S., Szymkowski D.E., and Bethea J.R. (2011) Inhibition of soluble tumor necrosis factor is therapeutic in experimental autoimmune encephalomyelitis and promotes axon preservation and remyelination. Brain 134:2736-2754.
Dvoriantchikova G., Barakat D., Brambilla R., Hernandez H., Bethea J.R., Shestopalov V.I., and Ivanov D. (2009) Inactivation of astroglial NF-kB promotes survival of retinal neurons following ischemic injury. Eur. J. Neurosci. 30:175-85.
Brambilla R.*, Hurtado A., Persaud T., Esham K., Pearse D.D., Oudega M., and Bethea J.R. (2009) Transgenic inhibition of astroglial NF-kB leads to increased axonal sparing and sprouting following spinal cord injury. J. Neurochem. 110:765-78.
Brambilla R.*, Persaud T., Hu X., Karmally K., Shestopalov V.I., Dvoriantchikova G., Ivanov D., Nathanson L., Barnum S.R., and Bethea J.R. (2009) Transgenic inhibition of astroglial NF-kB improves functional outcome in experimental autoimmune encephalomyelitis by suppressing chronic central nervous system inflammation. J. Immunol. 182:2628-40.
Brambilla R.*, Bracchi-Ricard V., Hu W.-H., Frydel B., Bramwell A., Karmally S., Green E.J., and Bethea J.R. (2005) Inhibition of astroglial nuclear factor kappaB reduces inflammation and improves functional recovery after spinal cord injury. J. Exp. Med. 202:145-56.
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