Neurorestorative therapy of stroke with agents that increase HDL

描述(申请人提供)：高密度脂蛋白胆固醇(高密度脂蛋白胆固醇)对血管内皮细胞和血管壁功能有积极作用。据我们所知，目前还没有研究将增加高密度脂蛋白胆固醇作为一种神经恢复疗法来促进中风后大脑可塑性和神经功能的恢复。基于强有力的初步数据，在卒中后一天开始给药时增加高密度脂蛋白胆固醇的药物，促进血管重塑并显著减少缺血性卒中后的功能缺陷，我们寻求开发一种新的缺血性卒中的神经修复治疗方法。在临床前大脑中动脉闭塞(MCAO)的啮齿动物模型中，设计了以下特定的目标和相关的假设来开发这种恢复性疗法，并研究其分子机制。目的1研究提高成年小鼠卒中后高密度脂蛋白胆固醇的药物的安全性、毒性和神经恢复作用。我们假设，在中风发病后一天开始用增加高密度脂蛋白-C(NIASPAN(N)和TO901317(T))的药物治疗中风小鼠可以改善神经功能恢复，并且是安全和耐受性良好的。毒性最小、更有效的促进卒中后功能转归的药物(NIASPAN或TO901317，N-或-T)将被确定并将用于以下目标2和3。目标2将阐明N-或-T治疗对卒中血管生成因子和血管重塑(即脑血流量(CBF)、血管生成和动脉生成)的调节作用。N-或-T诱导的血管重塑在卒中后功能结局中的作用将得到检验。我们推测，N或T治疗卒中可诱导内皮型一氧化氮合酶(ENOS)和血管生成素-1(Ang1)/Tie2信号活性，从而增加卒中后小鼠的脑血流量、血管生成和动脉生成。抗血管生成因子血管抑素(K1-5)抑制血管重塑，损害卒中后的功能结果，并减弱N-或-T诱导的卒中后恢复作用。目的3将确定N-或-T诱导中风后血管重塑和功能恢复的分子信号通路。利用eNOS基因敲除小鼠和抗Tie2抗体分别检测eNOS和Ang1/Tie2在N或T诱导的修复效应和血管重塑中的作用。其基本假设是：增加高密度脂蛋白-C制剂(N-or-T)通过增加脑组织eNOS和Ang1/Tie2信号的表达和激活来促进卒中后的功能恢复；这些因素通过诱导血管生成和动脉生成促进血管重构，从而促进功能恢复。这项研究提供了一种治疗中风的新的高效方法，并可能将我们的发现转化为对患者提高实验性中风中高密度脂蛋白-C的恢复性治疗益处的结果。公共卫生相关性：中风是导致发病率和长期残疾的第三大原因。高密度脂蛋白胆固醇(HDLC)对血管内皮细胞和血管壁功能有积极作用。基于强有力的初步数据，在卒中后一天开始给药时增加高密度脂蛋白胆固醇的药物，促进血管重塑并显著减少缺血性卒中后的功能缺陷，我们寻求开发一种新的缺血性卒中的神经修复治疗方法。尼斯潘和TO901317是提高高密度脂蛋白胆固醇的有效药物。因此，我们建议使用升高高密度脂蛋白-C的药物来开发中风的神经恢复疗法，并在临床前大脑中动脉闭塞(MCAO)的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，并可能允许将我们的发现翻译给患者。

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.