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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的患有糖尿病 (DM) 的缺血性卒中患者表现出独特的危险因素和病因学特征，并且神经血管预后比非糖尿病患者更差。因此，迫切需要进行调查糖尿病和非糖尿病人群中风后神经血管的变化并开发治疗方法专门设计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，与低高密度脂蛋白胆固醇（HDL-C）、 HDL-C 的抗氧化能力、内皮一氧化氮合酶 (p-eNOS) 的低磷酸化以及减少 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。然而，D-4F 对缺血性中风后的治疗作用没有被调查。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可改善 T2DM 和非 DM 小鼠神经功能的恢复，并增加缺血大脑中的 p-eNOS 和 ABCA1。以一种新颖且临床相关的方法，基于我们强大的根据初步数据，我们建议使用 D-4F 治疗非糖尿病和 T2DM 人群的中风老鼠。我们寻求开发 D-4F 作为一种新型神经恢复疗法，以减少白质 (WM) 功能障碍缺血性发作后 24 小时开始治疗时，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身上，而不是老年动物动物中，中风的流行人群。年龄的增长也会增加神经功能障碍中风。我们还开发并实施了多模态 MRI 成像，可以动态监测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 ABCA1 和 p-eNOS 信号传导活性，从而介导血管和 WM 重塑，并共同改善中风后的功能结果。因此，我们提出两个高度集成且纵向设计的具体目标。目标 1 将调查延迟的情况（中风后 24 小时）D-4F 对中风后年轻成年和老年小鼠非糖尿病和 T2DM 的治疗作用。脑卒中后脑WM和血管变化以及神经功能结果的差异将分析用或不用 D-4F 治疗的非 DM 和 T2DM 小鼠之间的差异。 MRI 将用于测量治疗反应和恢复背后的神经血管重组的动态。瞄准 2、使用eNOS基因敲除小鼠和特定脑ABCA1缺失小鼠，我们将通过以下方式研究其机制：其中 D-4F 促进神经血管重塑，从而促进神经功能恢复。长期目标该 RO1 旨在开发一种针对患有或不患有糖尿病的患者中风的神经恢复疗法。