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

摘要 合并糖尿病(DM)的缺血性卒中患者表现出明显的危险因素和病因学特征 神经血管预后较非糖尿病患者差。因此，迫切需要调查 糖尿病和非糖尿病人群卒中后神经血管的变化及其治疗方法的研究 专为减少中风后的神经缺陷而设计。2型糖尿病(T2 DM)占90% 糖尿病患者，并与低高密度脂蛋白胆固醇(HDL-C)相关， 高密度脂蛋白胆固醇的抗氧化能力，内皮型一氧化氮合酶(p-eNOS)的低磷酸化，以及 降低了ATP结合盒转运体A1(ABCA1)基因的表达。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对缺血性卒中后的治疗作用 没有被调查过。我们的初步数据显示，D-4F治疗卒中后2小时或24小时开始 缺血性卒中促进T2 DM和非DM小鼠神经功能的恢复 缺血脑组织中P-eNOS和ABCA1的表达。在一种新的和临床相关的方法中，基于我们的强健 初步数据，我们建议在非糖尿病和T2 DM人群中使用D-4F治疗中风 老鼠。我们寻求开发D-4F作为一种新的神经修复疗法来减少白质(WM)功能障碍 在T2 DM和非DM小鼠中，当在缺血发作后24小时开始治疗时，血管损伤 卒中。此外，大多数中风治疗方法的发展都集中在年轻成年动物身上，而不是老年动物身上。 动物，中风的流行人群。年龄的增加也会增加神经功能障碍 卒中。我们还开发并实现了可以动态监测的多模式MRI成像 动物和患者的神经血管重塑。在目前的研究中，我们将测量WM和 D-4F在青壮年和老年高血压动物模型中的血管变化及作用机制探讨 卒中后未发生T2 DM。我们的假设是，D-4F增加ABCA1和p-eNOS信号活性，从而 调节血管和WM重塑，并协同改善中风后的功能结局。因此，我们， 提出两个高度整合和纵向设计的具体目标。目标1将调查延迟的 (卒中后24小时)D-4F对非糖尿病和T2 DM的治疗作用。 卒中后脑白质和血管改变与神经功能结局的差异 将分析非糖尿病和T2 DM小鼠接受或不接受D-4F治疗的情况。核磁共振将用于 测量治疗反应和康复基础上的神经血管重组的动力学。在AIM 2、利用eNOS基因敲除小鼠和ABCA1小鼠脑内特异性缺失模型，研究其作用机制。 哪种D-4F可促进神经血管重塑，从而促进神经功能恢复。的长期目标是 这种RO1是为了开发一种神经恢复性治疗方法，用于治疗患有或不患有糖尿病的中风患者。

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.