Painful versus insensate diabetic neuropathy

疼痛性糖尿病神经病变与无知觉性糖尿病神经病变

• 批准号: 8987979
• 负责人: Douglas E Wright
• 金额: $ 33.03万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-01-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8987979
• 关键词: Address; Animal Model; Antibodies; Axon; Biological Markers; Biopsy; Burn injury; Clinical Trials; Complications of Diabetes Mellitus; Cutaneous; Development; Diabetes Mellitus; Diabetic Neuralgia; Diabetic Neuropathies; Diet; Disease; Epidermis; Equilibrium; Esthesia; Exercise; Fiber; Fibromyalgia; Frequencies; Functional disorder; Funding; Future; Goals; Grant; Healthcare; Human; In Vitro; Individual; Inflammation; Intervention; Ion Channel; Knowledge; Lead; Life Style; Longitudinal Studies; Mission; Modeling; Modification; Mus; Neuropathy; Neurophysiology - biologic function; Non-Insulin-Dependent Diabetes Mellitus; Numbness; Pain; Pain management; Patients; Peripheral; Peripheral Nervous System Diseases; Phenotype; Play; Population; Prediabetes syndrome; Predisposition; Prophylactic treatment; Public Health; Recruitment Activity; Relative (related person); Reporting; Research; Research Personnel; Risk; Rodent; Rodent Model; Running; Sensory; Skin; Specific qualifier value; Symptoms; Testing; Translating; burden of illness; care burden; chemotherapy induced neuropathy; chronic pain; diabetic; disability; human subject; improved; in vivo; mouse model; nerve supply; neurochemistry; neurotrophic factor; painful neuropathy; prevent; public health relevance; relating to nervous system; research study; translational study; treatment strategy

 DESCRIPTION (provided by applicant): Diabetic neuropathy (DN) is one of the most prevalent and debilitating complications of diabetes. However, DN remains largely an untreatable condition and current strategies only address pain control. A number of cellular mechanisms have been identified that lead to DN, but no explanation exists as to why certain patients develop pain, or alternatively develop insensate sensory loss. This paucity of information has hampered clinicians in developing prophylactic treatment strategies for patients that adequately prevent painful or insensate neuropathy. Our long-range goal is to understand how changes in peripheral axons can lead to varied sensory symptoms in diabetes. In previous funding years, we have identified rodent models that better reflect the varied symptoms of human DN and used these models to understand how changes in axonal subtypes within the epidermis may be related to specific symptoms of DN. Epidermal innervation is derived from two distinct axonal populations that are differentiated by different neurochemical markers and neurotrophic responsiveness. These two sensory axon subtypes are referred to as peptidergic or nonpeptidergic axons. We believe that key modifications occur in these epidermal axon subtypes early in the progression of DN that can lead to pain, or alternatively, loss of sensation. The central hypothesis is that the ratio and damage to two axonal subtypes innervating the skin is critical in specifying sensory dysfunction in diabetes. The aims of the grant include 1) testing whether changes in epidermal axons can drive pain or loss of sensation in diabetes, and testing whether inflammation and NGF responsible for changing epidermal axon phenotypes, 2) whether exercise intervention prevent or reverse changes in epidermal axon phenotypes, and 3) whether skin biopsy analyses be used to predict and follow epidermal changes associated with small fiber DN in humans. These proposed experiments are unique as they present a simple, but testable hypothesis that may explain how the divergent sensory complications can develop in diabetes. Importantly, our approaches are easily translatable to human studies and may be very relevant to other forms of neuropathy. The analyses of skin biopsies as performed here may provide new predictive power to identify patients at risk for developing neuropathy, and may also be used as a better indicator of neuropathy improvement in future clinical trials of diabetic neuropathy.

 描述（由申请人提供）：糖尿病神经病变（DN）是糖尿病最常见和最令人衰弱的并发症之一。然而，DN在很大程度上仍然是一种无法治疗的疾病，目前的策略仅涉及疼痛控制。已经确定了许多导致DN的细胞机制，但对于为什么某些患者会出现疼痛或出现无感觉的感觉丧失，还没有解释。这种信息的缺乏阻碍了临床医生为患者制定预防性治疗策略，以充分预防疼痛或感觉迟钝的神经病变。我们的长期目标是了解外周轴突的变化如何导致糖尿病患者的各种感觉症状。在过去的资助年中，我们已经确定了更好地反映人类DN各种症状的啮齿动物模型，并使用这些模型来了解表皮内轴突亚型的变化如何与DN的特定症状相关。表皮神经支配来源于两种不同的轴突群体，其通过不同的神经化学标记物和神经营养反应来区分。这两种感觉轴突亚型被称为肽能或非肽能轴突。我们认为，在DN进展的早期，这些表皮轴突亚型发生了关键的修饰，可能导致疼痛，或者感觉丧失。 中心假设是，比例和损害的两个轴突亚型支配皮肤是至关重要的，在指定感觉功能障碍的糖尿病。补助金的目的包括：1）测试 表皮轴突的变化是否可以在糖尿病中引起疼痛或感觉丧失，并测试炎症和NGF是否负责改变表皮轴突表型，2）运动干预是否预防或逆转表皮轴突表型的变化，以及3）皮肤活检分析是否用于预测和跟踪与人类小纤维DN相关的表皮变化。这些拟议的实验是独一无二的，因为它们提出了一个简单但可验证的假设，可以解释糖尿病中不同的感觉并发症是如何发展的。重要的是，我们的方法很容易转化为人类研究，可能与其他形式的神经病变非常相关。此处进行的皮肤活检分析可能提供新的预测能力，以识别有发生神经病变风险的患者，并且也可能在未来的糖尿病神经病变临床试验中用作神经病变改善的更好指标。