Clinically, ischemic stroke is recognized as a sexually dimorphic disease. Reproductive hormones are a major contributor to differences in male and female pathobiology. However, emerging data clearly show that outcome from stroke is shaped by biologic sex in addition to hormone exposure. The major hypothesis of this proposal is that distinct gender-based cell death programs are activated after an ischemic insult. We will investigate and identify molecular cell death pathways that are differentially regulated by gender. The overall goal of this proposal is to identify and evaluate the major pathways of cell death activated in male and female brain after in vivo middle cerebral artery occlusion (MCAO). We hypothesize that male cell death is mediated primarily by the caspase-independent activation of nitric oxide (NO), peroxynitrite formation, oxidant-induced DMA damage, and activation of PARP-1, leading to the release of apoptosis inducing factor (AIF) from mitochondria. In contrast, cell death in females is predominately caspase- dependent and secondary to ischemia-induced release of cytochrome C, activation of caspase-9 and formation of the apoptosome. Selective interference with each of these pathways will lead to different outcomes in males and females.
In Aim 1 we will examine hormonally controlled wild type (WT) and PARP-/- mice to determine the extent of AIF translocation. We will reduce AIF levels in animals of both genders and assess outcomes after stroke.
Aim 2 will evaluate cytochrome C release and caspase formation and determine the effect of caspase inhibition in both genders. Gender differences in X-linked inhibitor of apoptosis (XIAP) will be examined in Aim 3. Finally, in Aim 4 we will examine the production of reactive oxygen species (ROS) and bioenergetic markers in males and females. Relevance: Emerging pre-clinical data suggests that the fundamental pathways leading to cell death differ in males and females. Recently, gender differences in the response to pharmaceutical agents used to both prevent (aspirin) and treat (thrombolytics) stroke have been described. Understanding these differences will allow us to develop novel and more efficacious therapies that will enhance the health of stroke patients of both sexes.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-BINP-L (01))
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Bosetti, Francesca
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University of Connecticut
Schools of Medicine
United States
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Verma, Rajkumar; Cronin, Chunxia G; Hudobenko, Jacob et al. (2017) Deletion of the P2X4 receptor is neuroprotective acutely, but induces a depressive phenotype during recovery from ischemic stroke. Brain Behav Immun 66:302-312
Ritzel, Rodney M; Patel, Anita R; Spychala, Monica et al. (2017) Multiparity improves outcomes after cerebral ischemia in female mice despite features of increased metabovascular risk. Proc Natl Acad Sci U S A 114:E5673-E5682
Spychala, Monica S; Honarpisheh, Pedram; McCullough, Louise D (2017) Sex differences in neuroinflammation and neuroprotection in ischemic stroke. J Neurosci Res 95:462-471
Bravo-Alegria, Javiera; McCullough, Louise D; Liu, Fudong (2017) Sex differences in stroke across the lifespan: The role of T lymphocytes. Neurochem Int 107:127-137
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
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
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
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; 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

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