Targeting blood-derived integrin signaling after stroke

中风后靶向血液来源的整合素信号传导

• 批准号: 9923009
• 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
• 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/9923009
• 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; 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

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。我们发现雌性而不是雄性小鼠的血浆玻璃纤维素（VTN）水平增加 临时脑部动脉闭塞中风后遗传VTN缺失时的组织损失较小 （MCAO）。 VTN的这种特异性有害作用可能与女性有关 中风后的功能性神经结局。因此，该提议的重点是雌性小鼠。我们也发现 该VTN在MCAO之后泄漏到大脑，并诱导促炎性细胞因子的表达。我们的体外和 体内数据表明，VTN通过特定的AV整合蛋白起作用，并通过UPAR进行。整合素激活 细胞内信号通过局灶性粘合剂激酶（FAK）。雌鼠全身注射了FAK 中风后6小时抑制剂的结果更好。这些数据表明VTN-整合素蛋白-FAK 信号传导导致中风后组织损失。 AIM 1将确定个人差异是否 MCAO后观察到的血液中VTN水平的增加预测了炎症反应和脑组织的丧失。 这可能会提供额外的预后中风标记，并开放新的机会来开发治疗方法。 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fak来起作用，两个早期 响应者细胞类型对炎症有重大贡献。我们将确定最有效的 MCAO后的时间和使用FAK抑制剂的全身治疗持续时间，以改善结果，包括 长期的运动功能，还可以在年龄的“绝经后”雌性小鼠中对此进行测试，因为中风发生 主要在老年人中，更年期后的结果较差。 FAK抑制剂目前正在临床试验中 癌症，似乎耐受性良好。 AIM 2将定义特定VTN受体介导的程度 VTN效应，使用MCAO在体内后使用药物和遗传方法。这个目标将有助于 确定可能比FAK抑制更具选择性的分子靶标和治疗方法。 AIM 3将定义 据报道 男性以及中风后较高的血液IL-6水平是否有助于VTN的诱导。我们将 还确定女性马是否调节VTN以及VTN是否抵消了受保护的 雌激素和孕酮的作用。这些研究共同集中于新颖而独特的分子靶标 这会导致更糟的结果，并将为中风后开发药物治疗的新途径 也许是针对女性的。