Neurorestorative Strategy for Diabetic Peripheral Neuropathy

糖尿病周围神经病变的神经恢复策略

基本信息

批准号：
8591814
负责人：
FENG-QIAO LI
金额：
$ 22.51万
依托单位：
COGNOSCI, INC.
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-10 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8591814
关键词：
Activities of Daily Living Adult Advanced Glycosylation End Products Affect Alleles Amputation Animal Model Anti-Inflammatory Agents Anti-inflammatory Apolipoprotein E Atrophic Attenuated Axon Blood Circulation Calcium Cell Culture Techniques Cessation of life Cholesterol Complex Complication Complications of Diabetes Mellitus Data Demyelinations Development Diabetes Mellitus Diabetic Neuropathies Diabetic Retinopathy Disease Dyslipidemias E protein Genes Genetic Genetic Polymorphism Glucose Goals Growth Factor Human Hyperglycemia Hyperlipidemia In Vitro Inflammation Inflammatory Inflammatory Response Insulin-Dependent Diabetes Mellitus Investigational New Drug Application Knockout Mice Lead Legal patent Lipids Mediating Medical Microglia Modeling Multiple Sclerosis Mus N-Methylaspartate Nerve Crush Nerve Fibers Nerve Regeneration Neurites Neurodegenerative Disorders Neuroglia Neurons Neuropathy Non-Insulin-Dependent Diabetes Mellitus Outcome Measure Oxidative Stress Pain Pain management Pathogenesis Pathology Patients Peptides Peripheral Peripheral Nerves Peripheral Nervous System Diseases Phase Prevention strategy Property Protein Isoforms Proteins Quality of life Recovery of Function Risk Factors Role Series Spinal Ganglia Spinal cord injury Streptozocin Subarachnoid Hemorrhage Symptoms Testing Therapeutic Therapeutic Effect Toxic effect Translating Traumatic Brain Injury Treatment Efficacy United States Food and Drug Administration Vertebral column apolipoprotein E-3 apolipoprotein E-4 axon regeneration axonal degeneration biological adaptation to stress blood glucose regulation cholesterol transporters db/db mouse diabetic diabetic patient diabetic rat excitotoxicity foot genetic risk factor in vivo in vivo Model lipid transport macrophage mimetics nerve injury nervous system disorder neurorestoration neurotoxicity new therapeutic target novel phase 1 study preclinical safety prevent public health relevance receptor binding regenerative remyelination repaired sciatic nerve sound type I and type II diabetes

项目摘要

DESCRIPTION (provided by applicant): Diabetic peripheral neuropathy (DPN) is one of the most common and devastating complications of diabetes mellitus, affecting more than 50% of diabetic patients, and is the leading cause of foot amputation. DPN, characterized by peripheral axonal degeneration and demyelination, can be disabling and extremely painful, causing significant loss of functional abilities and decreasing quality of life. Currently, the only effectve treatments are glucose control and pain management. Although glucose control and some preventive strategies have been proposed to attenuate the development of DPN, none of them has demonstrated neuroreparative activity for existing neuropathy. Therefore, a neurorestorative strategy to repair damaged peripheral nerves is still critically needed to alleviate the persistent symptoms of established DPN. Cognosci has innovatively created and characterized a series of peptides derived from human apolipoprotein E (apoE), which we designate as "COG" compounds, from which we have identified a lead compound COG112 for inflammatory neurodegenerative diseases. Extensive studies have demonstrated that COG112 and other COG compounds exert potent neuroprotective activities against oxidative stress and inflammatory response, as well as neuroreparative activities both in vitro and in vivo. We have also obtained data showing that COG112 can significantly prevent axonal degeneration and promote axonal regeneration and remyelination in a sciatic nerve crush model. A similar neuroprotective effect has been validated in animal models of a variety of neurological disorders such as traumatic brain injury, spinal cord injury, subarachnoid hemorrhage and multiple sclerosis, implicating a therapeutic efficacy for these diseases. Because apoE has been considered as one of the genetic factors of diabetes and DPN, our preliminary data support that COG112 may demonstrate therapeutic efficacy on DPN by protecting peripheral nerves from hyperglycemia-mediated oxidative and inflammatory damages and promoting neuroregeneration. Therefore, we will test our hypothesis through both in vitro and in vivo models of DPN in the following specific aims: 1) To validate the potential neuroprotective effect of COG112 on a high glucose-induced neuronal death and axonal damage in primary dorsal root ganglion (DRG) cultures and the neuroregenerative effect on neurite outgrowth of DRGs from adult streptozocin (STZ)-induced diabetic rats. 2) To determine if COG112 exerts neuroprotective and neurorestorative effects in vivo by functional and histological examination in a DPN model of BKS db/db mice.

描述（由申请人提供）：糖尿病周围神经病变（DPN）是糖尿病最常见且最具破坏性的并发症之一，影响超过 50% 的糖尿病患者，并且是足部截肢的主要原因。 DPN 的特点是周围轴突变性和脱髓鞘，可能会导致残疾和极度疼痛，导致功能能力显着丧失并降低生活质量。目前，唯一有效的治疗方法是血糖控制和疼痛管理。尽管已经提出控制血糖和一些预防策略来减轻 DPN 的发展，但它们都没有表现出对现有神经病变的神经修复活性。因此，仍然迫切需要一种修复受损周围神经的神经修复策略来缓解持续存在的神经损伤。已建立的 DPN 的症状。 Cognosci 创新地创建并表征了一系列源自人类载脂蛋白 E (apoE) 的肽，我们将其命名为“COG”化合物，从中我们确定了治疗炎症性神经退行性疾病的先导化合物 COG112。广泛的研究表明，COG112 和其他 COG 化合物对氧化应激和炎症反应发挥有效的神经保护活性，以及体外和体内的神经修复活性。我们还获得的数据表明，COG112 在坐骨神经挤压模型中可以显着预防轴突变性并促进轴突再生和髓鞘再生。类似的神经保护作用已在多种神经系统疾病（如创伤性脑损伤、脊髓损伤、蛛网膜下腔出血和多发性硬化症）的动物模型中得到验证，表明对这些疾病的治疗功效。由于apoE被认为是糖尿病和DPN的遗传因素之一，我们的初步数据支持COG112可能通过保护周围神经免受高血糖介导的氧化和炎症损伤并促进神经再生来显示对DPN的治疗功效。因此，我们将通过 DPN 的体外和体内模型来检验我们的假设，具体目标如下：1）验证 COG112 对高糖诱导的初级背根神经节神经元死亡和轴突损伤的潜在神经保护作用（ DRG）培养物以及对成年链佐星（STZ）诱导的糖尿病大鼠 DRG 神经突生长的神经再生作用。 2) 通过在 BKS db/db 小鼠的 DPN 模型中进行功能和组织学检查来确定 COG112 是否在体内发挥神经保护和神经恢复作用。