Numerous neurological diseases are characterized by a sex difference. The neuropathology often includes infiltration of immune cells, with this immune infiltration potentially contributing to disease pathogenesis. Since it is known that sex differences exist in the immune system, this confounds investigations into sex differences in the CNS. Thus, we will use bone marrow chimeras to investigate sex differences in the CNS. By varying sex chromosomes or sex hormones in hosts reconstituted with a common immune system, one can ascertain the role of sex chromosomes and sex hormones on the brain response to injury. We will use one of the most inflammatory of all CNS disease models, the multiple sclerosis model, experimental autoimmune encephalomyelitis (EAE), to show applicability of this approach to a variety of neurological diseases. We will employ mice which differ in the complement of sex chromosomes (XX vs. XY), while having the same gonadal type, to determine the effect of sex chromosomes in the absence of confounding effects of exposure to different types of sex hormones. Specifically, in aim #1 we will determine whether the greater severity of EAE in XX, as compared to XY-, mice is due to sex chromosome effects in the CNS.
In aim #2, we will determine if the sex chromosome effect in the CNS during EAE is due to the dose of X or Y genes. Finally in aim #3, we will use mice which differ in gonadal type, female vs. male, while having the same sex chromosome complement (XX vs. XX Sry) to determine whether the greater severity of EAE in female, as compared to male, mice is due to sex hormone effects in the CNS.
This is an exploratory (R21) grant to determine the effect of sex chromosomes and sex hormones on the central nervous system's response to an immune attack using the multiple sclerosis model, experimental autoimmune encephalomyelitis. This proposal will establish a model system to determine the effect of sex chromosomes and sex hormones on a variety of neurological diseases characterized by a sex difference.
| 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 |
| Sasidhar, Manda V; Itoh, Noriko; Gold, Stefan M et al. (2012) The XX sex chromosome complement in mice is associated with increased spontaneous lupus compared with XY. Ann Rheum Dis 71:1418-22 |
| 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 |
| Spence, Rory D; Voskuhl, Rhonda R (2012) Neuroprotective effects of estrogens and androgens in CNS inflammation and neurodegeneration. Front Neuroendocrinol 33:105-15 |
| Voskuhl, Rhonda R; Gold, Stefan M (2012) Sex-related factors in multiple sclerosis susceptibility and progression. Nat Rev Neurol 8:255-63 |
