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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结