Role of bradykinin receptor 2 in tPA stroke therapy

缓激肽受体 2 在 tPA 中风治疗中的作用

• 批准号: 9767297
• 负责人: Fabricio Simao
• 金额: $ 21.47万
• 依托单位: JOSLIN DIABETES CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9767297
• 关键词: Address; Adoptive Transfer; Adverse effects; Affect; Aftercare; Agonist; Alteplase; Area; Blood - brain barrier anatomy; Blood Vessels; Blood specimen; Bone Marrow; Bone Marrow Cells; Bradykinin; Bradykinin Receptor; Brain; Brain hemorrhage; Cell Death; Cells; Cerebral hemisphere hemorrhage; Cerebrum; Chimera organism; Clinical; Coculture Techniques; Collaborations; Data; Development; Endothelial Cells; Endothelium; Endothelium-Dependent Relaxing Factors; Extravasation; FDA approved; Factor XII; Glucose; Goals; Grant; Growth and Development function; Hemorrhage; Hospitals; Human; Immune; Immune Cell Activation; Immune system; Immunobiology; Infarction; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Infusion procedures; Injury; Ischemic Stroke; K-Series Research Career Programs; Laboratories; Link; Mediating; Mentors; Mentorship; Molecular; Mus; Neurosciences; Oxygen; Pathway interactions; Patients; Phagocytosis; Plasma; Plasma Kallikrein; Plasminogen; Process; Prostate-Specific Antigen; Research; Research Personnel; Risk; Role; Series; Signal Transduction; Splenectomy; Stroke; Testing; Therapeutic; Thrombolytic Therapy; Time; Training; Treatment Efficacy; Wild Type Mouse; Writing; acute stroke; brain endothelial cell; career development; cell injury; deprivation; experimental study; improved; in vitro Model; in vitro activity; innovation; macrophage; migration; monocyte; neuron loss; new therapeutic target; novel; novel strategies; paracrine; post stroke; prevent; programs; recruit; skills; stroke therapy

Project Summary The widespread use of tissue plasminogen activator (tPA), the only FDA-approved acute stroke treatment, remains limited by its narrow therapeutic time window and related risks of brain hemorrhage. Bradykinin (BK) is well known for its actions as an endothelial-dependent vasodilator and a powerful proinflammatory agonist. A number of experimental studies have show that BK receptors are upregulated after stroke by mediating inflammatory effects during early stages after stroke, indicating that BK aggravates cerebral injury. In preliminary studies, we found that: 1) BK formation is increased after tPA therapy through plasma kallikrein activation; 2) co-administration of a BK receptor 2 antagonist with tPA treatment after stroke reduces hemorrhage transformation; 3) B2R agonist does not induce endothelial cell death during oxygen and glucose deprivation; 4) splenectomized or macrophage-depleted mice with tPA decreased brain hemorrhage; 5) BK infusion after stroke increases hemorrhage transformation, which was blocked in macrophage-depleted mice. The objective of the proposed studies is to define the mechanisms by which BK affects and activates macrophages after tPA therapy, thus causing brain hemorrhage via proinflammatory processes during vascular injury. Our ultimate goal is to delineate the mechanistic underpinnings of tPA therapy responsible for improving the time window and to render tPA safer and more widely usable in patients with stroke. We propose to test the following specific aims: (i) to determine the contribution of conditional endothelium- and macrophage-specific B2R deletion to tPA-induced hemorrhage transformation; (ii) to characterize the role of BK in activated macrophages on accumulation and recruitment after tPA treatment; (iii) to delineate the molecular mechanisms by which BK regulates macrophage function and its interaction with brain endothelial cells. I will use this mentored career development award (K01) to fulfill a series of training objectives, which build upon my prior skills in neuroscience, but also expand my expertise in ways, which are essential to my transition to independent investigator. The training component of this application will build on my expertise in the immune system by investigating vascular injury involved in brain hemorrhage after tPA therapy. Together with training in molecular immunobiology, this will enable me to establish my own cutting-edge research program in stroke. The career development activities will be mentored by Dr. George King in collaboration with Drs. Magdy Selim, Kazuhide Hawakaya, and Stephan Kissler because of their areas of scientific expertise, and the technical and scientific advice that I stand to gain from our mentoring relationship. My career development activities will be focused on: 1) mentorship and guidance on laboratory management and organization; 2) the development and growth of my independent research program; 3) institutional responsibilities and fulfilling requirements for promotion and expanding my scientific network; 4) grant writing skills.

项目摘要 组织纤溶酶原激活剂（TPA）的广泛使用，唯一的FDA急性急性中风治疗 仍然受到其狭窄的治疗时间窗口和脑出血的相关风险的限制。 Bradykinin（BK）是 以其作为内皮依赖性血管扩张剂和强大的促炎激动剂而闻名。一个 实验研究的数量表明，中风后BK受体被介导上调 中风后早期阶段的炎症作用，表明BK加剧了脑损伤。在 初步研究，我们发现：1）通过血浆Kallikrein TPA治疗后BK形成增加 激活; 2）BK受体2拮抗剂与中风后TPA处理的共同给药可减少 出血转化； 3）B2R激动剂不会在氧气和葡萄糖期间诱导内皮细胞死亡 剥夺; 4）用TPA的脾切除或巨噬细胞的小鼠减少了脑出血； 5）BK 中风后输注会增加出血转化，该转化在巨噬细胞耗尽的小鼠中被阻塞。 拟议研究的目的是定义BK影响和激活的机制 TPA治疗后的巨噬细胞，因此在血管期间通过促炎过程引起脑出血 受伤。我们的最终目标是描述负责改进的TPA疗法的机械基础 时间窗口和使TPA更安全，可在中风患者中更广泛地使用。我们建议测试 以下特定目的：（i）确定条件内皮和巨噬细胞特异性的贡献 B2R缺失对TPA诱导的出血转化； （ii）表征BK在激活中的作用 TPA治疗后积累和招募的巨噬细胞； （iii）描绘分子机制 BK调节巨噬细胞功能及其与脑内皮细胞的相互作用。我会用这个 指导的职业发展奖（K01）实现了一系列培训目标，这是我先前的 神经科学的技能，但也扩大了我的专业知识，这对于我过渡到 独立研究者。该应用程序的培训部分将基于我的免疫专业知识 通过研究TPA治疗后涉及脑出血的血管损伤。以及培训 在分子免疫生物学中，这将使我能够在中风中建立自己的尖端研究计划。 职业发展活动将由乔治·金博士与博士合作。 Magdy Selim， Kazuhide Hawakaya和Stephan Kissler的科学专业知识领域以及技术和技术领域 我将从我们的指导关系中获得的科学建议。我的职业发展活动将是 专注于：1）实验室管理和组织的指导和指导； 2）发展和 我独立研究计划的成长； 3）机构责任和满足要求 促进和扩展我的科学网络； 4）授予写作技巧。