Caveolin-1 and Altered Neuregulinism in Diabetic Neuropathy

Caveolin-1 和糖尿病神经病变中神经调节蛋白的改变

• 批准号: 7560385
• 负责人: Rick T Dobrowsky
• 金额: $ 31.68万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7560385
• 关键词: 1-Phosphatidylinositol 3-Kinase; Address; Adult; Affect; Afferent Neurons; Animal Model; Animals; Attention; Axon; Binding; Biochemical; Biology; Blood Vessels; Cell Culture Techniques; Cell Survival; Cell model; Cells; Cellular biology; Coculture Techniques; Complex; Critical Pathways; Data; Demyelinations; Dermal; Development; Diabetes Mellitus; Diabetic Neuropathies; Dominant-Negative Mutation; Down-Regulation; Doxycycline; Esthesia; Etiology; Event; Family; Fiber; Functional disorder; Gene Deletion; Genetic; Glucose; Goals; Growth Factor; Hyperglycemia; In Vitro; Insulin-Dependent Diabetes Mellitus; Kinetics; Knock-out; Knockout Mice; Leg; MAP Kinase Gene; Measures; Mechanics; Membrane Microdomains; Metabolic; Modeling; Molecular; Motor; Mus; Myelin Proteins; Myelinated nerve fiber; Natural regeneration; Nerve; Nerve Degeneration; Neural Conduction; Neuregulin 1; Neuregulins; Neuronal Dysfunction; Neurons; Nodal; Outcome Study; Pathologic; Peripheral Nerves; Peripheral Nervous System Diseases; Physiological; Production; Protein Isoforms; Protein Tyrosine Kinase; Proteome; Receptor Protein-Tyrosine Kinases; Reporting; Research; Role; Schwann Cells; Sensory; Series; Signal Transduction; Stimulation of Cell Proliferation; Stress; Structure; Structure of tibial nerve; Therapeutic; Transgenic Mice; Upper arm; Wild Type Mouse; Work; caveolin 1; diabetes control; diabetic; in vivo; insight; morphometry; mouse model; myelination; nerve supply; neuronal survival; neurotrophic factor; novel; public health relevance; response; sensory neuropathy; sural

DESCRIPTION (provided by applicant): The etiology of diabetic peripheral neuropathy (DPN) is complex and involves the degeneration of both neurons and Schwann cells (SCs). Although much attention has focused on how altered growth factor signaling contributes to neuronal dysfunction, a significant gap exists in our understanding of how hyper-glycemia affects gliotrophic factors. Neuregulin-1 (NRG1) is a gliotrophic growth factor that promotes cell survival, mitogenesis and myelination by activating Erb B receptor tyrosine kinases in developing SCs. In contrast, and relevant to the etiology of DPN, pathologic activation of Erb B2 in myelinated SCs can induce demyelination and the onset of peripheral neuropathies. Our broad hypothesis is that diabetes induces an "altered neuregulinism" that contributes to SC degeneration and the progression of DPN. In support of this hypothesis, we provide evidence that diabetes stimulates Erb B2 activity in peripheral nerve and that this correlates with the downregulation of a negative regulator of Erb B2, caveolin-1 (Cav-1). Using myelinated SC/sensory neuron co-cultures, we demonstrate that hyperglycemia decreases Cav-1 levels and enhances NRG1-induced demyelination. Cav-1 may contribute to the degeneration of myelinated axons in vivo as the rate of onset of a mechanical hypoalgesia was faster in diabetic Cav-1 knockout versus wild type mice. Similarly, we show that Erb B2 activity is sufficient to cause a decrease in motor nerve conduction velocity and induce a mechanical hypoalgesia using a novel SC-specific conditional transgenic mouse that upregulates a constitutively-active Erb B2 in response to doxycycline. Thus, our goal is to integrate findings from animal and cellular models to gain mechanistic insight into how pathologic activation of Erb B2 affects SCs and contributes to the onset of sensory dysfunctions in DPN. Our objectives are to: 1) determine the mechanism by which Cav- 1 enhances the degenerative effects of NRG1 under hyperglycemic conditions using myelinated SC/sensory neuron explants from wild type and Cav-1 null mice, 2) determine the necessity/sufficiency of Cav-1 in contributing to Erb B2 activation and the onset of DPN using Cav-1 null mice and 3) determine the effect of diabetes on NRG expression in diabetic nerve and ascertain the sufficiency of Erb B2 in contributing to sensory deficits using novel Erb B2 conditional transgenic mice. This work will provide a new paradigm toward understanding the effect of NRGs in modulating axo-glial interactions in DPN. PUBLIC HEALTH RELEVANCE: Diabetic peripheral neuropathy (DPN) results from the degeneration of nerves that transmit sensations from the legs and arms. Schwann cells (SCs) are specialized cells that closely associate with many nerves and also undergo profound changes in DPN. Our hypothesis is that prolonged hyperglycemic stress alters the response of SCs to growth factors called neuregulins. In adult myelinated nerve, neuregulins can induce demyelination, which contributes to DPN. Using a cell culture model of myelinated nerve, we have identified that glucose increases the degenerative effects of neuregulins. Thus, the objectives of this research are to determine if diabetes affects the expression and activity of neuregulins in diabetic nerve from mice and to identify the molecular events by which neuregulins may induce nerve degeneration. The expected outcome of these studies is that we will identify molecular interactions that may enhance the therapeutic benefit of growth factors in the treatment of DPN.

描述（由申请人提供）：糖尿病周围神经病变（DPN）的病因很复杂，涉及神经元和施万细胞（SC）的变性。尽管很多注意力都集中在生长因子信号传导的改变如何导致神经元功能障碍上，但我们对高血糖如何影响胶质营养因子的理解存在重大差距。 Neuregulin-1 (NRG1) 是一种胶质营养生长因子，通过激活发育中的 SC 中的 Erb B 受体酪氨酸激酶来促进细胞存活、有丝分裂和髓鞘形成。相反，与 DPN 的病因学相关的是，有髓鞘 SC 中 Erb B2 的病理激活可诱导脱髓鞘和周围神经病的发作。我们的广泛假设是，糖尿病会引起“神经调节蛋白功能改变”，从而导致 SC 变性和 DPN 进展。为了支持这一假设，我们提供的证据表明，糖尿病会刺激周围神经中的 Erb B2 活性，并且这与 Erb B2 的负调节因子 Caveolin-1 (Cav-1) 的下调相关。使用有髓鞘 SC/感觉神经元共培养，我们证明高血糖会降低 Cav-1 水平并增强 NRG1 诱导的脱髓鞘。 Cav-1 可能导致体内有髓轴突变性，因为与野生型小鼠相比，糖尿病 Cav-1 敲除小鼠机械痛觉减退的发生率更快。类似地，我们使用新型 SC 特异性条件转基因小鼠表明，Erb B2 活性足以引起运动神经传导速度降低并诱导机械痛觉减退，该转基因小鼠响应多西环素上调组成型活性 Erb B2。因此，我们的目标是整合动物和细胞模型的发现，以深入了解 Erb B2 的病理激活如何影响 SC 并导致 DPN 中感觉功能障碍的发生。我们的目标是：1) 使用来自野生型和 Cav-1 无效小鼠的有髓鞘 SC/感觉神经元外植体确定 Cav-1 在高血糖条件下增强 NRG1 退行性作用的机制，2) 确定 Cav 的必要性/充分性-1 使用 Cav-1 缺失小鼠促进 Erb B2 激活和 DPN 发作，3) 确定糖尿病对糖尿病神经中 NRG 表达的影响并确定使用新型 Erb B2 条件转基因小鼠，Erb B2 足以导致感觉缺陷。这项工作将为理解 NRGs 在调节 DPN 中轴突-胶质细胞相互作用中的作用提供一个新的范例。公众健康相关性：糖尿病周围神经病 (DPN) 是由传递腿部和手臂感觉的神经退化引起的。雪旺细胞 (SC) 是与许多神经密切相关的特殊细胞，在 DPN 中也会发生深刻的变化。我们的假设是，长期的高血糖应激会改变 SC 对称为神经调节蛋白的生长因子的反应。在成人有髓神经中，神经调节蛋白可诱导脱髓鞘，从而导致 DPN。使用有髓神经的细胞培养模型，我们发现葡萄糖会增加神经调节蛋白的退行性作用。因此，本研究的目的是确定糖尿病是否影响小鼠糖尿病神经中神经调节蛋白的表达和活性，并确定神经调节蛋白可能诱导神经变性的分子事件。这些研究的预期结果是我们将确定可能增强生长因子在 DPN 治疗中的治疗效果的分子相互作用。