Investigation of D-4F effects of neurovascular remodeling after diabetic stroke

摘要 糖尿病（DM）缺血性卒中患者表现出不同的危险因素和病因学特征， 神经血管预后比非DM患者差。因此，迫切需要调查 糖尿病和非糖尿病人群卒中后的神经血管变化，并开发治疗方法 专门用于减少中风后的神经功能缺损。2型糖尿病（T2DM）占90%， 糖尿病患者，并与低高密度脂蛋白胆固醇（HDL-C），损害的 HDL-C的抗氧化能力，内皮型一氧化氮合酶（p-eNOS）的低磷酸化， 降低ATP结合盒转运蛋白A1（ABCA1）基因表达。D-4F是一种经济的载脂蛋白 A-I（ApoA-I）模拟肽，目前用于临床试验，以减少冠状动脉粥样硬化， 急性冠脉综合征患者。然而，D-4F在缺血性卒中后的治疗效果， 没有被调查。我们的初步数据表明，D-4F治疗中风后2小时或24小时开始， 缺血性中风改善了T2DM和非DM小鼠的神经功能恢复， 缺血脑组织中p-eNOS和ABCA 1的表达。在一种新的和临床相关的方法中，基于我们强大的 根据初步数据，我们建议使用D-4F治疗非DM和T2DM人群的卒中， 小鼠我们寻求开发D-4F作为一种新的神经恢复疗法，以减少白色物质（WM）功能障碍 在缺血性脑损伤发作后24小时开始治疗时， 中风此外，大多数中风治疗的发展集中在年轻的成年动物上，而不是老年动物。 动物，中风的流行人群。年龄的增加也会增加神经功能障碍， 中风我们还开发和实施了多模态MRI成像，可以动态监测 在动物和患者中的神经血管重塑。在目前的研究中，我们将测量WM和 血管变化，并阐明D-4F在年轻成年和老年动物中的作用机制， 中风后无T2DM。我们的假设是D-4F增加ABCA 1和p-eNOS信号传导活性， 介导血管和WM重塑，并共同改善卒中后的功能结局。因此， 提出了两个高度集成和纵向设计的具体目标。目标1将调查延迟的 (24h中风后）D-4F在中风后的年轻成年和老年小鼠中的非DM和T2DM中的治疗作用。 脑卒中后WM与血管改变及神经功能预后的差异 将分析用或不用D-4F处理的非DM和T2DM小鼠之间的差异。MRI将用于 测量作为治疗反应和恢复基础的神经血管重组的动力学。在aim中 2、利用eNOS基因敲除小鼠和ABCA1特异性脑缺失小鼠，通过对小鼠脑组织中eNOS基因的表达进行研究，探讨eNOS基因敲除小鼠脑组织中ABCA1特异性脑缺失的机制。 其中D-4F促进神经血管重塑，从而促进神经恢复。的长期目标 本研究报告的目的是开发一种神经恢复疗法，用于治疗有或无糖尿病的中风患者。

ABSTRACT Ischemic stroke patients with Diabetes mellitus (DM) exhibit a distinct risk-factor and etiologic profile and a worse neurovascular prognosis than non-DM patients. Therefore, there is a compelling need to investigate neurovascular changes after stroke in the DM and non-DM population and to develop therapeutic approaches specifically designed to reduce neurological deficits after stroke. Type 2 diabetes (T2DM) constitutes 90% of diabetic patients and is associated with low high-density lipoprotein cholesterol (HDL-C), impairment of the anti-oxidative capacity of HDL-C, low phosphorylation of endothelial nitric oxide synthase (p-eNOS), and with reduced ATP-binding cassette transporter A1 (ABCA1) gene expression. D-4F is an economical apolipoprotein A-I (ApoA-I) mimetic peptide, presently employed in clinical trials to reduce coronary atherosclerosis in patients with acute coronary syndrome. However, the therapeutic effects of D-4F in post-ischemic stroke have not been investigated. Our preliminary data show that D-4F treatment of stroke starting 2h or 24h after ischemic stroke improves recovery of neurological function in both T2DM and non-DM mice and also increases p-eNOS and ABCA1 in the ischemic brain. In a novel and clinically relevant approach, based on our robust preliminary data, we propose to use D-4F in the treatment of stroke in the non-DM and T2DM population in mice. We seek to develop D-4F as a novel neurorestorative therapy to reduce white matter (WM) dysfunction and vascular damage, in T2DM and non-DM mice when treatment is initiated at 24h after onset of ischemic stroke. In addition, most development of stroke treatments has focused on young adult animals, but not on old animals, the prevalent population with stroke. Increased age also increases neurological impairment after stroke. We have also developed and implemented multimodality MRI imaging which can dynamically monitor neurovascular remodeling in both the animal and the patient. In the current study, we will measure WM and vascular changes and elucidate the mechanisms of action of D-4F in young adult and aged animals with and without T2DM after stroke. Our hypothesis is that D-4F increases ABCA1 and p-eNOS signaling activity which mediates vascular and WM remodeling and in concert improve functional outcome after stroke. We, therefore, propose two highly integrated and longitudinally designed Specific Aims. Aim 1 will investigate the delayed (24h after stroke) therapeutic effects of D-4F in non-DM and T2DM in young adult and aged mice after stroke. The differences in cerebral WM and vascular changes, and neurological functional outcome after stroke between non-DM and T2DM mice treated with or without D-4F will be analyzed. MRI will be employed to measure the dynamics of neurovascular reorganization underlying therapeutic response and recovery. In Aim 2, using eNOS knockout mice and specific loss of brain ABCA1 mice, we will investigate the mechanisms by which D-4F promotes neurovascular remodeling and hence, neurological recovery. The long-term objective of this RO1 is to develop a neurorestorative treatment for stroke in patients with or without diabetes.