Neurorestorative therapy of stroke with agents that increase HDL

使用增加 HDL 的药物进行中风的神经恢复治疗

• 批准号: 8217131
• 负责人: JIELI CHEN
• 金额: $ 28.58万
• 依托单位: HENRY FORD HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8217131
• 关键词: Adult; Agonist; Angiogenic Factor; Angiopoietin-1; Angiostatins; Antibodies; Attenuated; Blood Vessels; Brain; Cerebrovascular Circulation; Cerebrum; Clinical; Data; Drug Formulations; Fostering; Health; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Hour; Ischemic Stroke; Knockout Mice; Liver; Mediating; Middle Cerebral Artery Occlusion; Molecular; Morbidity - disease rate; Mus; Nervous System Physiology; Neurologic; Neurological outcome; Nicotinic Acids; Pathway interactions; Patients; Pharmaceutical Preparations; Pre-Clinical Model; Recovery; Recovery of Function; Regulation; Rodent Model; Role; Safety; Serum; Signal Pathway; Signal Transduction; Stroke; TIE-2 Receptor; Testing; Therapeutic; Tissues; Toxic effect; Translations; Vascular Endothelial Cell; Vascular Endothelial Growth Factors; Vascular remodeling; angiogenesis; base; design; disability; functional outcomes; human NOS3 protein; improved; neurorestoration; novel; pre-clinical; receptor; stroke therapy

DESCRIPTION (provided by applicant): High-density lipoprotein cholesterol (HDL-C) has a positive effect on endothelial cell and vascular wall function. To our knowledge, there are no studies investigating the use of increasing HDL-C as a neurorestorative therapy to promote brain plasticity and recovery of neurological function after stroke. Based on robust preliminary data that agents which increase HDL-C when administered starting one day after stroke, promote vascular remodeling and significantly reduce functional deficits after ischemic stroke, we seek to develop a novel neurorestorative treatment of ischemic stroke. The following specific aims and associated hypotheses are designed to develop this restorative therapy and to investigate their molecular mechanisms in a pre-clinical rodent model of middle cerebral artery occlusion (MCAo). Aim 1 will investigate safety, toxicity and neurorestorative effects of select agents which increase HDL-C after stroke in adult mice. We hypothesize that treatment of stroke in mice with agents that increase HDL-C {Niaspan (N) and TO901317 (T)} initiated at one day after stroke onset improves neurological functional recovery, and is safe and well tolerated. The minimally toxic and more effective agent (Niaspan or TO901317, N-or-T) that promotes functional outcome after stroke will be identified and will be employed in the following Aims 2 & 3. Aim 2 will elucidate the effect of N-or-T treatment of stroke on the regulation of angiogenic factors and vascular remodeling, i.e. cerebral blood flow (CBF), angiogenesis, and arteriogenesis. The contribution of vascular remodeling induced by N-or-T in functional outcome after stroke will be tested. We hypothesize that N-or-T treatment of stroke induces endothelial nitric oxide synthase (eNOS) and Angiopoietin-1(Ang1)/Tie2 signaling activity, which increase CBF, angiogenesis and arteriogenesis after stroke in mice. Inhibition of vascular remodeling by an anti-angiogenic factor, Angiostatin (K1-5), impairs functional outcome after stroke and attenuates the N-or-T induced restorative effect after stroke in mice. Aim 3 will identify the molecular signaling pathways by which N- or-T induces vascular remodeling and functional recovery after stroke. The contribution of eNOS and Ang1/Tie2 to N-or-T induced restorative effect and vascular remodeling will be examined by using eNOS knockout mice and a specific antibody to Tie2 in mice subjected to stroke and treated with N-or- T, respectively. The underlying hypotheses are that: Increasing HDL-C agent (N-or-T) fosters functional recovery after stroke by increasing the expression and activation of eNOS and Ang1/Tie2 signaling in cerebral tissue; these factors promote vascular remodeling via the induction of angiogenesis and arteriogenesis, which augment functional recovery. This study provides a new and highly effective way to treat stroke and may permit translation of our findings of the restorative therapeutic benefit of agents which increase HDL-C in experimental stroke to the patient. PUBLIC HEALTH RELEVANCE: Stroke is the third leading cause of morbidity and long-term disability. High-density lipoprotein cholesterol (HDL-C) has a positive effect on endothelial cell and vascular wall function. Based on robust preliminary data that agents which increase HDL-C when administered starting one day after stroke, promote vascular remodeling and significantly reduce functional deficits after ischemic stroke, we seek to develop a novel neurorestorative treatment of ischemic stroke. Niaspan and TO901317 are effective medications for increasing HDL-C. Thus, we propose to develop neurorestorative therapy for stroke using agents that increase HDL-C and to investigate their molecular mechanisms in a pre-clinical rodent model of middle cerebral artery occlusion (MCAo). This study provides a new and highly effective way to treat stroke and may permit translation of our findings to the patient.

描述（由申请人提供）：高密度脂蛋白胆固醇（HDL-C）对内皮细胞和血管壁功能具有积极作用。据我们所知，尚无研究研究增加HDL-C作为一种神经训练疗法来促进中风后神经功能的恢复。基于强大的初步数据，该数据从中风后一天开始施用时会增加HDL-C的药物，促进血管重塑并在缺血性中风后显着减少功能缺陷，我们试图开发一种新型的对缺血性卒中的神经性治疗方法。以下特定目的和相关的假设旨在开发这种恢复性疗法，并在大脑中动脉闭塞（MCAO）的临床前啮齿动物模型中研究其分子机制。 AIM 1将研究成年小鼠中风后增加HDL-C的精选药物的安全性，毒性和神经疏松作用。我们假设用增加HDL-C {Niaspan（n）和To901317（t）}的药物对中风的治疗方法在中风发作后的一天启动，可以改善神经功能恢复，并且安全且耐受性良好。将确定促进中风后促进功能结果的最小有毒和更有效的药物（Niaspan或TO901317，N-OR-T）将被鉴定出来，并将在以下目的2和3中使用。AIM2将阐明n-or-t治疗中风治疗对杂种和血管生成因子和血管的重塑（cere）ceere flow（cere）的影响（cer）。动脉生成。 N-OR-T在中风后功能结果中诱导的血管重塑的贡献将被测试。我们假设中风的N或-T处理会诱导内皮一氧化氮合酶（ENOS）和血管生成素-1（ANG1）/TIE2信号活性，从而增加了小鼠中风后CBF，血管生成和动脉生成。通过抗血管生成因子Angiostatin（K1-5）抑制血管重塑，损害了中风后的功能结果，并减弱了小鼠中风后N-OR-T诱导的恢复效果。 AIM 3将确定N-OR-T诱导中风后血管重塑和功能恢复的分子信号通路。通过使用ENOS基因敲除小鼠和一种特异性抗体对eNOS和ANG1/TIE2对N-或T诱导的恢复效果和血管重塑的贡献，分别在患有中风并用N-或T处理的小鼠中对TIE2进行了特异性抗体。潜在的假设是：增加HDL-C试剂（N-OR-T）通过增加eNOS和ANG2/TIE2信号在脑组织中的表达和激活而促进了中风后的功能恢复；这些因素通过诱导血管生成和动脉生成来促进血管重塑，从而增强功能恢复。这项研究提供了一种治疗中风的新的高效方法，并可以允许转化我们对药物的恢复性治疗益处的发现，这些治疗剂增加了HDL-C向患者增加实验性中风。公共卫生相关性：中风是发病和长期残疾的第三主要原因。高密度脂蛋白胆固醇（HDL-C）对内皮细胞和血管壁功能具有积极作用。基于强大的初步数据，该数据从中风后一天开始施用时会增加HDL-C的药物，促进血管重塑并在缺血性中风后显着减少功能缺陷，我们试图开发一种新型的对缺血性卒中的神经性治疗方法。 Niaspan和TO901317是增加HDL-C的有效药物。因此，我们建议使用增加HDL-C并研究其分子机制的药物来开发中风的神经训练疗法，以在大脑中动脉闭塞（MCAO）的临床前啮齿动物模型中研究其分子机制。这项研究提供了一种治疗中风的新的高效方法，并可以将我们的发现转化给患者。