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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Midcareer Investigator Award in Patient-Oriented Research (K24)
Project #
5K24NS062117-05
Application #
8247805
Study Section
NST-2 Subcommittee (NST)
Program Officer
Utz, Ursula
Project Start
2008-04-01
Project End
2013-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
5
Fiscal Year
2012
Total Cost
$146,459
Indirect Cost
$10,849
Name
University of California Los Angeles
Department
Neurology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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
Kim, Roy Y; Hoffman, Alexandria S; Itoh, Noriko et al. (2014) Astrocyte CCL2 sustains immune cell infiltration in chronic experimental autoimmune encephalomyelitis. J Neuroimmunol 274:53-61
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
Wisdom, Amy J; Cao, Yuan; Itoh, Noriko et al. (2013) Estrogen receptor-β ligand treatment after disease onset is neuroprotective in the multiple sclerosis model. J Neurosci Res 91:901-8
Spence, Rory D; Wisdom, Amy J; Cao, Yuan et al. (2013) Estrogen mediates neuroprotection and anti-inflammatory effects during EAE through ERα signaling on astrocytes but not through ERβ signaling on astrocytes or neurons. J Neurosci 33:10924-33
Ziehn, Marina O; Avedisian, Andrea A; Dervin, Shannon M et al. (2012) Estriol preserves synaptic transmission in the hippocampus during autoimmune demyelinating disease. Lab Invest 92:1234-45
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
MacKenzie-Graham, Allan; Rinek, Gilda A; Avedisian, Andrea et al. (2012) Cortical atrophy in experimental autoimmune encephalomyelitis: in vivo imaging. Neuroimage 60:95-104
Spence, Rory D; Voskuhl, Rhonda R (2012) Neuroprotective effects of estrogens and androgens in CNS inflammation and neurodegeneration. Front Neuroendocrinol 33:105-15
Ziehn, Marina O; Avedisian, Andrea A; Dervin, Shannon M et al. (2012) Therapeutic testosterone administration preserves excitatory synaptic transmission in the hippocampus during autoimmune demyelinating disease. J Neurosci 32:12312-24

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