Matrix Metalloproteinase Inhibitors in Stroke

基质金属蛋白酶抑制剂在中风中的应用

基本信息

批准号：
7845519
负责人：
Gary Allen Rosenberg
金额：
$ 22.35万
依托单位：
UNIVERSITY OF NEW MEXICO
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-15 至 2011-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7845519
关键词：
3-Dimensional Alteplase Animal Model Animals Arts Astrocytes Attenuated Behavior Behavioral Biological Assay Blood - brain barrier anatomy Blood Vessels Brain Brain Hypoxia-Ischemia Cause of Death Cell Culture Techniques Cell Death Cells Cerebral hemisphere hemorrhage Cessation of life Clinical Clinical Trials Coculture Techniques Cultured Cells Drug Design Edema Enzyme Inhibition Event Funding Gelatinase A Gelatinase B Generations Goals Hemorrhage Hour Human Hypoxia In Vitro Infarction Injury Isotopes Kinetics Laboratories Lead Legal patent Long-Term Effects Magnetic Resonance Imaging Matrix Metalloproteinase Inhibitor Matrix Metalloproteinases Measurement Measures Mediating Methods Modeling Molecular Neuroglia Neurologic Patients Pharmaceutical Preparations Phase Prevention Recombinants Recovery Resources Risk Safety Screening procedure Simulate Stroke System Technology Testing Therapeutic Therapeutic Agents Toxic effect Wound Healing angiogenesis base behavior test design disability drug candidate drug discovery human MMP14 protein improved in vitro testing in vivo neurogenesis neuroinflammation novel prevent programs public health relevance translational clinical trial treatment trial

项目摘要

DESCRIPTION (provided by applicant): Stroke is the major neurological illness and recombinant tissue type plasminogen activator (rtPA) is the only approved treatment. Use of rtPA is limited to three hours after stroke because of the risk of intracerebral hemorrhage. Toxicity of rtPA occurs when the blood-brain barrier (BBB) is opened. Prevention of the BBB damage expands the therapeutic window for the use of rtPA in stroke. Matrix metalloproteinases (MMPs) are increased in brain after hypoxic/ischemic injury: MMPs disrupt the blood-brain barrier (BBB), causing edema, hemorrhage, and cell death. Others and the PI have shown that treatment with MMP inhibitors (MMPIs) prevent the early opening of the BBB and reduce death and hemorrhage in animal models of stroke. We propose to use in vitro screening of a number of novel MMPIs that have been patented by the Co-PI, and to test the most promising ones in animal models of stroke. The goal is to identify MMPIs that could be used to obtain an IND for translational clinical trials in the U01 program. Our goal is to rationally design, synthesize, and test MMPIs that could be used in treatment trials of MMPIs in stroke. These compounds block the MMPs involved in opening the BBB in the early phases of injury and may expand the therapeutic window for rtPA treatment. We plan to use in vitro methods to screen a large number of possible drugs. Those with the ability to block the BBB will be tested in vivo with isotopes. When several candidate drugs are identified, MRI will be used to simulate the clinical conditions with noninvasive studies of the early and subacute events, allowing for and behavioral testing in the same animals to assure that there is no interference with long- term recovery. Specific aims: 1) To develop and test in vitro the efficacy of the potential therapeutic agents that block the MMPs, using enzyme inhibition kinetic assays and 3-dimensional human brain microvascular endothelial and astrocyte or glia cell co-culture systems. 2) To determine the ability and efficacy of a new generation of MMP inhibitors (MMPIs) recently developed and patented by Sang and colleagues to block the early opening of the BBB as assessed by isotopes and MRI in animal models. 3) To select promising agents that block the BBB and to measure the effect on stroke infarct size at 48 hrs when the damage is greatest. 4) To further select the most efficacious agents for testing long-term effects on behavior, recovery, and survival in animal models. Significance: MMPIs protect the BBB and have been shown to extend the therapeutic window for use of rtPA in animal studies. This proposal will combine the resources of experts in MMPI drug design and measurements of BBB damage in vivo and will utilize start-of-art MRI technology to identify the most efficacious novel MMPIs for testing during the early phases of stroke. The goal of this two-year drug discovery project is to identify one or more lead compounds for later testing under the full U01 mechanism. PUBLIC HEALTH RELEVANCE: Stroke is the leading neurological cause of death and disability. Treatment with rtPA has been proven beneficial, but a constricted therapeutic window limits its use. Animal studies have shown that matrix metalloproteinase inhibitors (MMPIs), which reduce damage to the blood-brain barrier (BBB), attenuate the toxicity of rtPA and expand the therapeutic window. This project combines the expertise of a MMPI synthesis laboratory and a group with expertise in animal models of stroke. The goal is to identify several lead compounds that can be used in clinical trials. Novel MMPIs will be screened in cell cultures and cell-based models of the BBB. Promising agents will be tested in animals with isotopes. Finally, those agents that pass these initial studies will be tested with MRI measurements of BBB and infarct size with the addition of behavioral studies to show long-term recovery. The overall goal is to identify lead compounds that are patentable and can be used to obtain IND approval. Promising compounds would be useful for U01- funded clinical trials.

描述（由申请人提供）：中风是主要的神经系统疾病，重组组织型纤溶酶原激活剂（RTPA）是唯一的批准治疗方法。由于脑出血的风险，RTPA的使用限制为中风后三个小时。当打开血脑屏障（BBB）时，会发生RTPA的毒性。预防BBB损伤会扩大治疗窗口，用于使用RTPA中风。缺氧/缺血性损伤后，大脑的基质金属蛋白酶（MMP）增加：MMP破坏血脑屏障（BBB），导致水肿，出血和细胞死亡。其他人和PI表明，用MMP抑制剂（MMPI）的治疗可防止BBB的早期开放，并减少中风动物模型中的死亡和出血。我们建议在co-Pi专利的许多新型MMPI上使用体外筛选，并测试中风动物模型中最有前途的MMPI。目的是识别可用于在U01计划中获得转化临床试验的IND的MMPI。我们的目标是合理设计，合成和测试MMPI，这些MMPI可用于中风中MMPI的治疗试验。这些化合物阻止了在损伤的早期阶段开放BBB参与的MMP，并可能扩大治疗窗口进行RTPA治疗。我们计划使用体外方法来筛选大量可能的药物。那些能够用同位素在体内测试具有阻止BBB的人。当发现几种候选药物时，将使用对早期和亚急性事件的无创研究来模拟临床条件，从而使同一动物的早期和行为测试确保不会干扰长期恢复。具体目的：1）使用酶抑制动力学测定法和3维人脑微血管内皮细胞和星形胶质细胞或神经胶质细胞共文化系统，在体外开发和测试阻断MMP的潜在治疗剂的功效。 2）确定新一代MMP抑制剂（MMPI）最近由Sang及其同事授权的，以阻止动物模型中同位素和MRI评估的BBB的早期开放。 3）选择有望阻止BBB并在损害最大时在48小时时对中风梗塞大小的影响的有希望的药物。 4）进一步选择最有效的药物来测试对动物模型中行为，恢复和生存的长期影响。意义：MMPIS保护BBB，并已证明可以扩展用于在动物研究中使用RTPA的治疗窗口。该提案将结合MMPI药物设计专家的资源和体内BBB损害的测量，并将利用ART启动MRI技术来确定在中风早期阶段进行测试的最有效的新型MMPI。这个为期两年的药物发现项目的目的是确定一种或多种铅化合物，以在整个U01机制下进行以后测试。公共卫生相关性：中风是死亡和残疾的主要神经原因。用RTPA治疗已被证明有益，但是治疗窗口限制了其使用。动物研究表明，基质金属蛋白酶抑制剂（MMPI）减少了对血脑屏障（BBB）的损害，减轻RTPA的毒性并扩大治疗窗口。该项目结合了MMPI合成实验室的专业知识和具有中风动物模型专业知识的小组。目的是确定可以在临床试验中使用的几种铅化合物。新型MMPI将在BBB的细胞培养物和基于细胞的模型中进行筛选。有希望的药物将在具有同位素的动物中进行测试。最后，通过对BBB和梗死大小的MRI测量进行测试，通过添加行为研究以显示长期恢复。总体目标是确定可专利的铅化合物，可用于获得IND批准。有希望的化合物对于U01资助的临床试验将很有用。