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

D-4F对糖尿病脑卒中后神经血管重塑作用的研究

• 批准号: 9308346
• 负责人: JIELI CHEN
• 金额: $ 43.15万
• 依托单位: HENRY FORD HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-15 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9308346
• 关键词: ATP-Binding Cassette Transporters; Abbreviations; Acute; Adult; Aftercare; Age; Animals; Apolipoprotein A-I; Attenuated; Biological; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain hemorrhage; Cerebrovascular Circulation; Cerebrum; Clinical Trials; Coronary; Coronary Arteriosclerosis; Data; Development; Diabetes Mellitus; Distal; Etiology; Exhibits; Functional disorder; Gene Expression; Genes; Goals; Health; High Density Lipoprotein Cholesterol; Image; Impairment; Investigation; Ischemic Stroke; Knock-out; Knockout Mice; Lesion; Magnetic Resonance Imaging; Measurement; Measures; Mediating; Methods; Microvascular Dysfunction; Middle Cerebral Artery Occlusion; Monitor; Mus; NOS3 gene; Nervous System Physiology; Neurites; Neurologic; Neurologic Deficit; Non-Insulin-Dependent Diabetes Mellitus; Pathway interactions; Patients; Phosphorylation; Population; Recovery; Recovery of Function; Risk Factors; Severities; Signal Pathway; Signal Transduction; Stroke; Structure; Testing; Therapeutic; Therapeutic Effect; Vascular Permeabilities; White Matter Hyperintensity; acute coronary syndrome; aged; base; brain tissue; clinically relevant; design; diabetic; diabetic patient; experience; functional improvement; functional outcomes; high risk; imaging biomarker; improved; longitudinal design; macrovascular disease; mature animal; multimodality; neurological recovery; neurorestoration; neurovascular; non-diabetic; novel; outcome forecast; peptidomimetics; post stroke; stroke treatment; treatment response; white matter; white matter change; white matter damage; young adult

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.

抽象的 糖尿病（DM）缺血性卒中患者表现出明显的风险因素和病因学特征和A 与非DM患者相比，神经血管预后差。因此，有迫切需要调查 DM和非DM种群中风后的神经血管变化，并开发治疗方法 专门设计用于减少中风后神经缺陷。 2型糖尿病（T2DM）占90％ 糖尿病患者，与低密度脂蛋白胆固醇（HDL-C）相关，损害 HDL-C的抗氧化能力，内皮一氧化氮合酶（P-ENOS）的低磷酸化以及与氧化能力 减少了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 急性冠状动脉综合征患者。但是，D-4F在缺血后中风的治疗作用具有 没有被调查。我们的初步数据表明，D-4F的中风处理2h或24h之后 缺血性中风改善了T2DM和非DM小鼠的神经功能的恢复，也增加 缺血性大脑中的P-Enos和ABCA1。在一种新颖的临床相关方法中，基于我们的强大 初步数据，我们建议在非DM和T2DM种群中使用D-4F治疗中风 老鼠。我们试图将D-4F作为一种新型神经训练疗法来减少白质（WM）功能障碍 当缺血发作后24小时开始治疗时，在T2DM和非DM小鼠中的血管损伤 中风。此外，大多数中风治疗的发展都集中在年轻的成年动物上，但不关注老年人 动物，流行的中风。年龄增加也会增加神经系统障碍 中风。我们还开发并实施了多模式MRI成像，可以动态监视 动物和患者的神经血管重塑。在当前的研究中，我们将测量WM和 血管变化并阐明D-4F在年轻的成年和老年动物中的作用机制， 中风后没有T2DM。我们的假设是D-4F增加了ABCA1和P-Enos信号传导活性，这 介导血管和WM重塑，并在协同过程中改善中风后的功能结果。因此，我们 提出了两个高度集成和纵向设计的特定目标。 AIM 1将调查延迟 （中风后24小时）D-4F对非DM和T2DM的治疗作用在中风后年轻小鼠和老年小鼠。 脑WM和血管变化的差异以及中风后神经功能结果 将分析接受或没有D-4F处理的非DM和T2DM小鼠之间。 MRI将被雇用 测量神经血管重组的动力学基础治疗反应和恢复。目标 2，使用eNOS敲除小鼠和脑ABCA1小鼠的特定损失，我们将通过 D-4F促进了神经血管的重塑，因此促进了神经系统恢复。长期目标的 该RO1是为患有或患有糖尿病患者的中风开发神经训练治疗。