Stroke or Brain Attack is a sexually dimorphic disease. Our work of the last ten years emphasizes that sensitivity to cerebral ischemia, i.e. neuronal damage once an ischemic event has occurred, is sex - specific. We have closely modeled sex -linked differences in experimental stroke outcomes for many complex animal models, and in all cases, males must cope with a basal """"""""ischemia- sensitive"""""""" phenotype while females enjoy neuroprotection. This competitive renewal breaks new ground by focusing on biological sex differences in experimental ischemia, if sexual dimorphism in adult stroke is shaped by testosterone, and if this shaping occurs early in life. We hypothesize that one key effector of sex differences in cerebral ischemia is the steroid-producing astrocyte. New preliminary data indicate that astrocytes cultured from female rat or mouse brain are resistant to oxygen-glucose deprivation (OGD), while male astrocytes are highly vulnerable.
(Aim 1) tests the hypothesis that testosterone treatment increases ischemic damage from middle cerebral artery occlusion in male but not female rat.
(Aim 2) will detemline if sex steroid exposure within a key period of sexual brain development is important to sex-specific stroke sensitivity and tests the effect of fetal and neonatal brain masculinization on ischemic outcomes in the adult rat. We then test the hypothesis that female cortical or striatal astrocytes are less sensitive to OGD than male astrocytes and that male sensitivity is imprinted in the fetus (Aim 3) by testosterone and its metabolism to dihydrotestosterone (DHT) via the enzyme 5 alpha reductase (Aim 4). Lastly, we will utilize a unique strain of mice with targeted deletion of the sry gene (sex-determining region gene) and compare the importance of genetic sex (female XX vs male XY chromosomes) to the presence of gonadal steroids per se in ischemic outcome. Our findings will elucidate the mechanisms behind a most fundamental """"""""genetic"""""""" aspect of ischemia, biological sex.
| Li, Jun; Siegel, Matt; Yuan, Mike et al. (2011) Estrogen enhances neurogenesis and behavioral recovery after stroke. J Cereb Blood Flow Metab 31:413-25 |
| Zhu, W; Wang, L; Zhang, L et al. (2010) Isoflurane preconditioning neuroprotection in experimental focal stroke is androgen-dependent in male mice. Neuroscience 169:758-69 |
| Liu, Mingyue; Dziennis, Suzan; Hurn, Patricia D et al. (2009) Mechanisms of gender-linked ischemic brain injury. Restor Neurol Neurosci 27:163-79 |
| McCullough, Louise D; Koerner, Ines P; Hurn, Patricia D (2009) Effects of gender and sex steroids on ischemic injury. Handb Clin Neurol 92:149-69 |
| Cheng, Jian; Hu, Weidong; Toung, Thomas J et al. (2009) Age-dependent effects of testosterone in experimental stroke. J Cereb Blood Flow Metab 29:486-94 |
| Subramanian, Sandhya; Zhang, Bing; Kosaka, Yasuharu et al. (2009) Recombinant T cell receptor ligand treats experimental stroke. Stroke 40:2539-45 |
| Offner, H; Vandenbark, A A; Hurn, P D (2009) Effect of experimental stroke on peripheral immunity: CNS ischemia induces profound immunosuppression. Neuroscience 158:1098-111 |
| Liu, Mingyue; Oyarzabal, Esteban A; Yang, Rui et al. (2008) A novel method for assessing sex-specific and genotype-specific response to injury in astrocyte culture. J Neurosci Methods 171:214-7 |
| Dziennis, Suzan; Yang, Dongren; Cheng, Jian et al. (2008) Developmental exposure to polychlorinated biphenyls influences stroke outcome in adult rats. Environ Health Perspect 116:474-80 |
| Vagnerova, Kamila; Koerner, Ines P; Hurn, Patricia D (2008) Gender and the injured brain. Anesth Analg 107:201-14 |
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