Our work over the last fifteen years emphasizes that the cellular and molecular pathobiology of cerebral ischemia is strongly influenced by sex and by estrogen deficiency. This renewal application targets an exceptionally understudied area of stroke research that will be of interest to stroke nursing: interactions between the recovering brain and stroke-induced immune dysfunction in the female. It is now increasingly clear that human stroke results in multi-organ systemic disease, rather than in solely brain damage. While patients may survive the initial brain insult, many succumb to CNS injury-induced immunodepression and fatal infection. In animal-based studies, stroke-induced immunopathology is a bi-phasic molecular process of first stimulation, then degeneration, of lymphiod tissue that houses immune cells. Because all previous work has been conducted in male animals or in cells derived from male tissue, we know virtually nothing about these processes in the female. Our overall hypothesis is that focal stroke leads to abnormal activation of splenic immunocytes, particularly T lymphocytes that have a regulatory phenotype (CD4+CD25+FoxP3+ Treg cells) and ordinarily provide endogenous immunosuppression. Subsequently, there is a progressive apoptosis of the spleen, with broad destruction of most constituent immunologically competent cells but a sparing of Treg cells. We hypothesize that this relative overabundance of Treg cells mediates post-ischemic, systemic immunosuppression in the surviving animal. Invasion by splenic lymphocyte subsets into injured brain also results in two opposing contributions: 1) enhanced local inflammation and macrophage recruitment by non-Treg cells yet 2) a limiting of T cell-mediated brain damage by Treg cell suppressive mechanisms. In the female operating in an estradiol (E2)-depleted physiology, this pathology is exacerbated and puts the animal at exceptional risk. We propose to: 1) determine if peripheral immune dysfunction occurs in tandem with cerebral inflammation after focal cerebral ischemia (middle cerebral artery occlusion or MCAO) in the young adult and middle aged, reproductively senescent (RS) female mouse. The hypotheses are that a) focal stroke leads to early splenic activation, cytokine-mediated splenic apoptosis and loss of cell-mediated immunocompetence and b) estrogen deficiency exacerbates this pathology; 2) determine if peripheral T lymphocytes play a significant role in post-ischemic brain and spleen tissue outcomes and in behavioral deficits in the female. The hypotheses are: a) the T cells that contribute to stroke damage are specific for brain antigens, b) blocking translocation of non-Treg cell subsets to brain improves brain outcome and c) conditional deletion of Foxp3+ T reg cells aborts splenic destruction but at the high cost of increased brain injury;3) evaluate a novel G protein-coupled estrogen receptor 30 (GPR30) agonist for neuro- and immunoprotection after MCAO in the female. The hypothesis to be tested is that GPR30 agonist G1, like E2, alters Treg induction, mitigating immunosuppression while concurrently protecting the recovering brain.

Public Health Relevance

Stroke is a major killer of women in the US. Our study is focused on developing therapy that will improve brain outcomes and immune system function after stroke in females. We will also explore the effects of estrogen deficiency and restoration on post-stroke immunity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Nursing Research (NINR)
Type
Research Project (R01)
Project #
5R01NR003521-21
Application #
8300028
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Tully, Lois
Project Start
1993-12-10
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
21
Fiscal Year
2012
Total Cost
$370,923
Indirect Cost
$125,898
Name
University of Texas Austin
Department
None
Type
Schools of Arts and Sciences
DUNS #
170230239
City
Austin
State
TX
Country
United States
Zip Code
78712
Hurn, Patricia D (2014) 2014 Thomas Willis Award Lecture: sex, stroke, and innovation. Stroke 45:3725-9
Nobile, Cameron W; Palmateer, Julie M; Kane, Jackie et al. (2014) Impaired limb reaction to displacement of center of gravity in rats with unilateral striatal ischemic injury. Transl Stroke Res 5:562-8
Herson, Paco S; Palmateer, Julie; Hurn, Patricia D (2013) Biological sex and mechanisms of ischemic brain injury. Transl Stroke Res 4:413-9
Ren, Xuefang; Akiyoshi, Kozaburo; Grafe, Marjorie R et al. (2012) Myelin specific cells infiltrate MCAO lesions and exacerbate stroke severity. Metab Brain Dis 27:7-15
Ren, Xuefang; Akiyoshi, Kozaburo; Vandenbark, Arthur A et al. (2011) CD4+FoxP3+ regulatory T-cells in cerebral ischemic stroke. Metab Brain Dis 26:87-90
Dziennis, Suzan; Mader, Sarah; Akiyoshi, Kozaburo et al. (2011) Therapy with recombinant T-cell receptor ligand reduces infarct size and infiltrating inflammatory cells in brain after middle cerebral artery occlusion in mice. Metab Brain Dis 26:123-33
Jia, Jia; Verma, Saurabh; Nakayama, Shin et al. (2011) Sex differences in neuroprotection provided by inhibition of TRPM2 channels following experimental stroke. J Cereb Blood Flow Metab 31:2160-8
Dziennis, Suzan; Akiyoshi, Kozaburo; Subramanian, Sandhya et al. (2011) Role of dihydrotestosterone in post-stroke peripheral immunosuppression after cerebral ischemia. Brain Behav Immun 25:685-95
Ren, Xuefang; Akiyoshi, Kozaburo; Vandenbark, Arthur A et al. (2011) Programmed death-1 pathway limits central nervous system inflammation and neurologic deficits in murine experimental stroke. Stroke 42:2578-83
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

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