Cholinergic constraint and diabetic neuropathy

胆碱能限制和糖尿病神经病变

基本信息

批准号：
8877248
负责人：
NIGEL A. CALCUTT
金额：
$ 31.44万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
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：
2013-07-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8877248
关键词：
Acetylcholine Adult Afferent Neurons American Axon Back Biological Assay Biological Markers Biopsy Cessation of life Clinical Research Clinical Trials Complications of Diabetes Mellitus Confocal Microscopy Cornea Culture Media Data Development Diabetes Mellitus Diabetic Neuropathies Distal Early Diagnosis Eye FDA approved Goals Growth Growth Cones Health Image In Vitro Ligands Mitochondria Modeling Muscarinic Acetylcholine Receptor Muscarinic M1 Receptor Muscarinics Myopia Natural regeneration Nerve Neurites Neurons Neuropathy Newly Diagnosed Patients Peripheral Peripheral Nerves Peripheral Nervous System Diseases Phenotype Pirenzepine Presynaptic Terminals Process Rattus Rodent Rodent Model Sensory Signal Transduction Skin Solutions System Testing Therapeutic Therapeutic Agents Translating Translations Treatment Efficacy Work autocrine axon growth cholinergic diabetic diabetic patient in vivo indexing keratinocyte novel therapeutic intervention preclinical efficacy prevent research study type I and type II diabetes

项目摘要

DESCRIPTION (provided by applicant): Peripheral neuropathy is the most common complication of diabetes and will afflict over half of the 25 million Americans who currently suffe from diabetes. There is no FDA-approved therapy to prevent neuropathy or reverse the distal degenerative neuropathy already present in many newly diagnosed diabetic patients. Recent clinical and experimental studies have emphasized that retraction of the peripheral terminals of small sensory axons as an early feature of diabetic neuropathy. This offers a window of opportunity to halt or reverse the dying-back of peripheral terminals before neuronal death. We have recently discovered that muscarinic M1 receptor antagonists can enhance axonal outgrowth from adult rat sensory neurons grown under defined in vitro conditions and also prevent distal neuropathy in diabetic rodents. This prompts us to propose that adult peripheral neurons are under constant cholinergic constraint that moderates the growth capacity of axon terminals and that manipulating this endogenous system offers a novel therapeutic approach to reversing early diabetic neuropathy. We will investigate the mechanism of cholinergic constraint in adult sensory neurons and determine whether diabetes alters this process as part of the pathogenic mechanism of diabetic neuropathy. We will also demonstrate the therapeutic potential of manipulating this endogenous cholinergic constraint mechanism to reverse established distal neuropathy in diabetic rodents and use corneal confocal microscopy to illustrate that preclinical efficacy of a therapeutic can be rapidly translated to demonstrable efficacy in diabetic subjects with peripheral neuropathy.

描述（由申请人提供）：周围神经病变是糖尿病最常见的并发症，目前患有糖尿病的 2500 万美国人中有一半以上会受到周围神经病变的影响。目前还没有 FDA 批准的治疗方法来预防神经病变或逆转许多新诊断的糖尿病患者中已经存在的远端退行性神经病变。最近的临床和实验研究强调，小感觉轴突的外周末端回缩是糖尿病神经病变的早期特征。这提供了在神经元死亡之前停止或逆转外周末梢消退的机会之窗。我们最近发现，毒蕈碱 M1 受体拮抗剂可以增强在特定体外条件下生长的成年大鼠感觉神经元的轴突生长，还可以预防糖尿病啮齿动物的远端神经病变。这促使我们提出，成人周围神经元处于持续的胆碱能限制下，这会调节轴突末端的生长能力，并且操纵这种内源性系统为逆转早期糖尿病神经病变提供了一种新的治疗方法。我们将研究成人感觉神经元胆碱能约束的机制，并确定糖尿病是否改变了这一过程，作为糖尿病神经病变致病机制的一部分。我们还将证明操纵这种内源性胆碱能约束机制来逆转糖尿病啮齿动物中已建立的远端神经病变的治疗潜力，并使用角膜共聚焦显微镜来说明治疗的临床前疗效可以快速转化为患有周围神经病变的糖尿病受试者的可证明疗效。