Clinically, ischemic stroke is recognized as a sexually dimorphic disease. Most international databases consistently demonstrate that women have lower stroke incidence relative to men until advanced age. However, elderly women have higher morbidity and mortality compared to age-matched men once a stroke occurs. Aging enhances the inflammatory response to stroke, and recent data demonstrate that this effect is significantly more pronounced in females. Reproductive hormones clearly contribute to such differences in male and female pathobiology, however, the hormonal environment does not fully account for ischemic sexual dimorphism as tissue damage and functional outcome after an induced stroke are influenced by biologic sex in addition to the hormonal milieu. Emerging data has shown that the mechanisms that trigger cell death differ in males and females. We will utilize genetically manipulated ("Four Core Genotype") mice to dissociate the effects of chromosomal sex from that of gonadal hormones on stroke outcome in young animals (Aim 1);determine the effect of manipulating neonatal hormone levels on adult infarct damage (Aim 2);and investigate sex and hormone contributions to post-stroke inflammation in the 4CG mice (Aim 3) using a well established middle cerebral artery occlusion (MCAO) model of stroke. The overall goal of this proposal is to determine the genetic and hormonal (organizational and activational effects) contributions to stroke sensitivity across the lifespan. Identification of sex selective cell death mechanisms has significant translational relevance, as neuroprotective agents that are efficacious in one sex may exacerbate injury in the other. As recent clinical trials have shown variable efficacy of drugs in male and female patients, developing "sex- specific" therapeutic targets may improve our ability to treat stroke patients of both sexes.

Public Health Relevance

There is considerable evidence from both clinical and experimental studies that outcomes after stroke differ in males and females. New experimental data has shown that brain cells die differently in the male versus the female brain, and each sex responds differently to neuroprotective strategies. As stroke is now the number one cause of disability, new treatments are urgently needed.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS055215-07
Application #
8401524
Study Section
Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
Program Officer
Koenig, James I
Project Start
2006-04-01
Project End
2016-12-31
Budget Start
2013-01-01
Budget End
2013-12-31
Support Year
7
Fiscal Year
2013
Total Cost
$467,159
Indirect Cost
$155,253
Name
University of Connecticut
Department
Neurosciences
Type
Schools of Medicine
DUNS #
022254226
City
Farmington
State
CT
Country
United States
Zip Code
06030
Verma, Rajkumar; Harris, Nia M; Friedler, Brett D et al. (2016) Reversal of the Detrimental Effects of Post-Stroke Social Isolation by Pair-Housing is Mediated by Activation of BDNF-MAPK/ERK in Aged Mice. Sci Rep 6:25176
Ritzel, Rodney M; Crapser, Joshua; Patel, Anita R et al. (2016) Age-Associated Resident Memory CD8 T Cells in the Central Nervous System Are Primed To Potentiate Inflammation after Ischemic Brain Injury. J Immunol 196:3318-30
McCullough, Louise D; Mirza, Mehwish A; Xu, Yan et al. (2016) Stroke sensitivity in the aged: sex chromosome complement vs. gonadal hormones. Aging (Albany NY) 8:1432-41
Venna, Venugopal Reddy; McCullough, Louise D (2015) Role of social factors on cell death, cerebral plasticity and recovery after stroke. Metab Brain Dis 30:497-506
Friedler, Brett; Crapser, Joshua; McCullough, Louise (2015) One is the deadliest number: the detrimental effects of social isolation on cerebrovascular diseases and cognition. Acta Neuropathol 129:493-509
Mirza, Mehwish A; Ritzel, Rodney; Xu, Yan et al. (2015) Sexually dimorphic outcomes and inflammatory responses in hypoxic-ischemic encephalopathy. J Neuroinflammation 12:32
Manwani, Bharti; Bentivegna, Kathryn; Benashski, Sharon E et al. (2015) Sex differences in ischemic stroke sensitivity are influenced by gonadal hormones, not by sex chromosome complement. J Cereb Blood Flow Metab 35:221-9
Venna, Venugopal Reddy; Verma, Rajkumar; O'Keefe, Lena M et al. (2014) Inhibition of mitochondrial p53 abolishes the detrimental effects of social isolation on ischemic brain injury. Stroke 45:3101-4
Roy-O'Reilly, Meaghan; McCullough, Louise D (2014) Sex differences in stroke: the contribution of coagulation. Exp Neurol 259:16-27
Liu, Fudong; McCullough, Louise D (2014) The middle cerebral artery occlusion model of transient focal cerebral ischemia. Methods Mol Biol 1135:81-93

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