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Targeting blood-derived integrin signaling after stroke

中风后靶向血液来源的整合素信号传导

基本信息

批准号：
10155592
负责人：
THEO HAGG
金额：
$ 32.38万
依托单位：
EAST TENNESSEE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-15 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10155592
关键词：
Acute Affect Binding Blood Blood Proteins Brain Cells Corpus striatum structure Data Disease Dose Estrogens Extracellular Matrix Extravasation Female Focal Adhesion Kinase 1 Future Genetic Grant Hormones In Vitro Individual Differences Infiltration Inflammation Inflammatory Inflammatory Response Injections Integrins Interleukin-6 Lead Leukocytes Liver Measures Mediating Menopause Middle Cerebral Artery Occlusion Molecular Target Mus Neurological outcome Outcome Ovariectomy Peptides Pharmacological Treatment Pharmacology Pharmacotherapy Plasma Play Postmenopause Production Progesterone Proteins Recovery of Function Reporting Role Signal Pathway Signal Transduction Stroke Testing Time Tissues Treatment Protocols Urokinase Urokinase Plasminogen Activator Receptor Vitronectin Vitronectin Receptors Woman aged brain tissue cancer clinical trial cell type cytokine drug testing efficacious treatment female sex hormone functional outcomes genetic approach improved improved outcome in vivo inhibitor/antagonist insight kinase inhibitor macrophage male molecular targeted therapies mutant nervous system disorder novel post stroke prognostic protective effect receptor

项目摘要

Project Summary. We found that female, but not male, mice have increased plasma vitronectin (VTN) levels and less tissue loss upon genetic VTN deletion after a stroke by temporary middle cerebral artery occlusion (MCAO). This female-specific detrimental role of VTN may be relevant to women because that have worse functional neurological outcomes after stroke. Therefore, this proposal focuses on female mice. We also find that VTN leaks into the brain after MCAO and induces pro-inflammatory cytokine expression. Our in vitro and in vivo data suggest that VTN acts through specific av integrins and possibly through uPAR. Integrins activate intracellular signaling through focal adhesion kinase (FAK). Female mice injected systemically with an FAK inhibitor 6 h after a stroke had better much better outcomes. These data suggest that VTN-Integrin-FAK signaling contributes to tissue loss after stroke. Aim 1 will determine whether individual differences in increased VTN levels in the blood seen after MCAO predict the inflammatory response and loss of brain tissue. This might provide an additional prognostic stroke marker and open new opportunities to develop treatments. We will also determine whether VTN and FAK inhibition act through astroglial or microglial FAK, two early responder cell types with known significant contributions to inflammation. We will identify the most efficacious post-MCAO time and duration of systemic treatments with the FAK inhibitor to improve outcomes, including long-term locomotor function and also test this in aged “post-menopausal” female mice because stroke occurs mainly in older people, with worse outcomes after menopause. FAK inhibitors are currently in clinical trials for cancer and seem to be well tolerated. Aim 2 will define the extent to which the specific VTN receptors mediate the VTN effects, using pharmacological and genetic approaches after MCAO in vivo. This aim will help to identify molecular targets and treatments that may be more selective than FAK inhibition. Aim 3 will define whether the higher IL-6 induction in the female brain after MCAO is neuroprotective, as has been reported for males, and whether blood IL-6 levels, which are higher after stroke, contribute to induction of VTN. We will also determine whether female sex hormones regulate VTN and whether VTN counteracts the protective effects of estrogen and progesterone. Together, these studies focus on a novel and unique molecular target that contributes to worse outcomes, and will provide new avenues for developing drug treatments after stroke, perhaps specifically for women.

项目总结。我们发现雌性小鼠的血浆玻璃体粘连蛋白（VTN）水平升高，而雄性小鼠则没有