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.

项目摘要。我们发现雌性小鼠而非雄性小鼠的血浆玻连蛋白 (VTN) 水平升高。中风后暂时性大脑中动脉闭塞导致 VTN 基因缺失，从而减少组织损失 (MCAO)。VTN 的这种女性特有的疼痛作用可能与女性相关，因为女性的疼痛更严重。因此，我们还发现该提案主要针对雌性小鼠。我们的体外和研究表明，VTN 在 MCAO 后渗入大脑并诱导促炎细胞因子表达。体内数据表明，VTN 通过特定的 av 整合素发挥作用，并可能通过整合素激活。通过全身注射 FAK 的雌性小鼠进行细胞内信号传导。中风后 6 小时抑制剂具有更好的结果。这些数据表明 VTN-Integrin-FAK 具有更好的结果。信号传导导致中风后组织损失的目标 1 将确定个体差异是否存在。 MCAO 后血液中 VTN 水平升高可预测炎症反应和脑组织损失。这可能提供额外的中风预后标记，并为开发治疗方法开辟新的机会。我们还将确定 VTN 和 FAK 抑制是否通过星形胶质细胞或小胶质细胞 FAK（两种早期的我们将确定对炎症有显着贡献的应答细胞类型。 MCAO 后使用 FAK 抑制剂进行全身治疗以改善结果的时间和持续时间，包括长期运动功能，并在老年“绝经后”雌性小鼠中进行测试，因为中风发生主要针对老年人，FAK 抑制剂目前正在进行临床试验，绝经后预后较差。目标 2 将定义特定 VTN 受体介导的程度。在 MCAO 体内使用药理学和遗传学方法来观察 VTN 的效果将有助于这一目标。确定可能比 Aim 3 抑制更具选择性的分子靶点和治疗方法。 MCAO 后女性大脑中较高的 IL-6 诱导是否具有神经保护作用，正如已报道的那样男性，以及中风后较高的血液 IL-6 水平是否有助于诱导 VTN。还确定女性性激素是否调节 VTN 以及 VTN 是否抵消保护作用这些研究共同关注雌激素和黄体酮的影响。这会导致更糟糕的结果，并将为开发中风后药物治疗提供新途径，也许专门针对女性。