Neurorestorative therapy of stroke with agents that increase HDL

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有积极作用。据我们所知，目前还没有研究调查使用增加HDL-C作为神经恢复性治疗来促进脑可塑性和脑卒中后神经功能的恢复。基于可靠的初步数据，中风后一天开始使用的药物可增加HDL-C，促进血管重塑并显着减少缺血性中风后的功能缺陷，我们寻求开发一种新的缺血性中风神经恢复性治疗方法。以下具体目标和相关假设旨在发展这种恢复性治疗，并在临床前啮齿动物大脑中动脉闭塞（MCAo）模型中研究其分子机制。目的1将研究增加成年小鼠中风后HDL-C的药物的安全性、毒性和神经恢复作用。我们假设在中风发作后一天开始使用增加HDL-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，并且是安全且耐受性良好的。在接下来的目标2和3中，我们将确定一种毒性最小且更有效的药物（Niaspan或TO901317， N-or-T）来促进脑卒中后的功能结局。目的2将阐明n或t治疗脑卒中对血管生成因子和血管重塑的调节作用，即脑血流量（CBF）、血管生成和动脉生成。我们将测试n或t诱导的血管重构在脑卒中后功能预后中的作用。我们假设，脑卒中的n或t治疗诱导内皮一氧化氮合酶（eNOS）和血管生成素-1(Ang1)/Tie2信号活性，从而增加脑卒中后小鼠的CBF、血管生成和动脉生成。抗血管生成因子血管抑制素（K1-5）抑制血管重塑，损害脑卒中后的功能结果，减弱脑卒中后n或t诱导的恢复作用。目的3将确定脑卒中后N- or-T诱导血管重构和功能恢复的分子信号通路。eNOS和Ang1/Tie2对n或T诱导的恢复作用和血管重构的贡献将分别通过eNOS敲除小鼠和对中风小鼠和n或-T治疗小鼠的Tie2特异性抗体进行检测。潜在的假设是：增加HDL-C剂（n或t）通过增加脑组织中eNOS和Ang1/Tie2信号的表达和激活来促进脑卒中后功能恢复；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。本研究为治疗中风提供了一种新的、高效的方法，并可能使我们的研究结果转化为增加实验性中风患者HDL-C的药物的恢复性治疗益处。公共卫生相关性：中风是导致发病和长期残疾的第三大原因。高密度脂蛋白胆固醇（HDL-C）对内皮细胞和血管壁功能有积极作用。基于可靠的初步数据，中风后一天开始使用的药物可增加HDL-C，促进血管重塑并显着减少缺血性中风后的功能缺陷，我们寻求开发一种新的缺血性中风神经恢复性治疗方法。Niaspan和TO901317是提高HDL-C的有效药物。因此，我们建议使用增加HDL-C的药物开发中风的神经修复疗法，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。这项研究为治疗中风提供了一种新的、高效的方法，并可能将我们的发现转化为患者。

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.