This K24 Award application is designed to provide the PI with the time and resources to expand her clinical research efforts and to mentor trainees in this endeavor. In the past decade, Dr. Voskuhl's laboratory has made central findings related to sex hormone treatment in the animal model of multiple sclerosis (MS). Based on these findings, she designed and gained funding for a small pilot clinical trial, then a large multicenter, double-blind, placebo-controlled clinical trial, to treat women with MS using estriol pills. These trials attempt to recapitulate the protective effect of high levels of estriol during late pregnancy, with late pregnancy being a known time of relative protection from MS relapses.
Aim 1 will examine immune mechanisms during this multicenter trial by determining whether estriol treatment induces neuroprotective growth factor production by peripheral blood immune cells (PBMCs) derived from subjects in this trial. It will also assess whether estriol treatment decreases matrix metalloproteinases in PBMCs or increases CD4+CD25+ suppressor T cells. Dr. Voskuhl has also just completed a pilot clinical trial in men with MS using treatment with a testosterone gel. This attempts to recapitulate the protective effect of high testosterone levels in young men.
Aim 1 will provide the time and resources for the PI to design the follow up, larger, multicenter, double- blind, placebo-controlled clinical trial to treat men with MS using testosterone. It will also use PBMCs available from the recently completed testosterone pilot trial to determine whether testosterone treatment induces neuroprotective growth factor production by PBMCs. In this K24 Award, Dr. Voskuhl will mentor trainees in clinical immunology studies as well as in clinical trial design. Together these studies will assess the efficacy and mechanism of gender tailored sex hormone treatments in MS. If treatment with sex hormones is shown to induce neurotrophic factor production by immune cells, this would have implications for not only for MS, but also for other neurodegenerative diseases. If treatment with sex hormones is shown to down-regulate matrix matalloproteinases and increase CD4+CD25+ suppressor T cells, this would have implications for not only MS, but also for other cell mediated autoimmune diseases.
|Kurth, Florian; Luders, Eileen; Sicotte, Nancy L et al. (2014) Neuroprotective effects of testosterone treatment in men with multiple sclerosis. Neuroimage Clin 4:454-60|
|Du, Sienmi; Itoh, Noriko; Askarinam, Sahar et al. (2014) XY sex chromosome complement, compared with XX, in the CNS confers greater neurodegeneration during experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A 111:2806-11|
|Wisdom, Amy J; Cao, Yuan; Itoh, Noriko et al. (2013) Estrogen receptor-* ligand treatment after disease onset is neuroprotective in the multiple sclerosis model. J Neurosci Res 91:901-8|
|Voskuhl, Rhonda R; Gold, Stefan M (2012) Sex-related factors in multiple sclerosis susceptibility and progression. Nat Rev Neurol 8:255-63|
|MacKenzie-Graham, Allan J; Rinek, Gilda A; Avedisian, Andrea et al. (2012) Estrogen treatment prevents gray matter atrophy in experimental autoimmune encephalomyelitis. J Neurosci Res 90:1310-23|
|Spence, Rory D; Voskuhl, Rhonda R (2012) Neuroprotective effects of estrogens and androgens in CNS inflammation and neurodegeneration. Front Neuroendocrinol 33:105-15|
|MacKenzie-Graham, Allan; Rinek, Gilda A; Avedisian, Andrea et al. (2012) Cortical atrophy in experimental autoimmune encephalomyelitis: in vivo imaging. Neuroimage 60:95-104|
|Du, Sienmi; Sandoval, Francisco; Trinh, Pauline et al. (2011) Estrogen receptor-* ligand treatment modulates dendritic cells in the target organ during autoimmune demyelinating disease. Eur J Immunol 41:140-50|
|Mangiardi, Mario; Crawford, Daniel K; Xia, Xiaoyu et al. (2011) An animal model of cortical and callosal pathology in multiple sclerosis. Brain Pathol 21:263-78|
|Spence, Rory D; Hamby, Mary E; Umeda, Elizabeth et al. (2011) Neuroprotection mediated through estrogen receptor-alpha in astrocytes. Proc Natl Acad Sci U S A 108:8867-72|
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