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（DPN）的病因很复杂，涉及神经元和Schwann细胞（SCS）的退化。尽管很多关注集中在生长因子信号传导如何导致神经元功能障碍的方式上，但我们对高血糖如何影响伴醇型因素的理解存在很大的差距。 Neuregulin-1（NRG1）是一种神经营养的生长因子，通过激活ERB B受体酪氨酸激酶在发育中的SC中促进细胞的存活，有丝分裂和髓鞘。相反，与DPN的病因有关，髓鞘SC中ERB B2的病理激活可以诱导脱髓鞘和周围神经病的发作。我们广泛的假设是糖尿病诱导了“改变的神经调节症”，这有助于SC变性和DPN的进展。为了支持这一假设，我们提供了证据表明糖尿病刺激周围神经中的ERB B2活性，并且这与ERB B2，Caveolin-1（Caveolin-1（Cav-1）的负调节剂的下调相关）。使用髓鞘的SC/感觉神经元共培养，我们证明高血糖降低CAV-1水平并增强NRG1诱导的脱髓鞘。 CAV-1可能会导致体内髓鞘轴突的变性，因为在糖尿病性cav cav-1敲除与野生型小鼠相比，机械性低敏感性的发作速度更快。同样，我们表明ERB B2活性足以引起运动神经传导速度的降低，并使用一种新型的SC特异性条件转基因小鼠诱导机械性低敏性，该小鼠响应强力霉素，从而上调了组成性活跃的ERB B2。因此，我们的目标是整合来自动物和细胞模型的发现，以获取机械洞察力，了解ERB B2的病理激活如何影响SCS并有助于DPN中感觉功能障碍的发作。我们的目标是：1）确定使用髓样和cav-1 null小鼠的髓鞘SC/感觉神经元在高血糖条件下增强NRG1在高血糖条件下增强NRG1的退化作用的机制，2）确定Cav-1在使用ERB B2激活以及使用Cav-1 Null Cavn null Cave null cave null cave null cave null cave null cav null cave null cav null cave null cav null cave null cav null cave and Cav-null Mipe seploce and Cav-null Mipe seption的必要性/足够性。糖尿病神经并确定ERB B2在使用新型ERB B2条件转基因小鼠中导致感觉缺陷的充分性。这项工作将为理解NRG在调节DPN中的Axo-Glial相互作用方面的影响提供新的范式。公共卫生相关性：糖尿病周围神经病（DPN）是由于神经退化引起的，从腿和手臂传递感觉。 Schwann细胞（SC）是与许多神经紧密相关的专门细胞，并且在DPN发生了深刻的变化。我们的假设是，长时间高血糖应激改变了SC对称为神经素的生长因子的反应。在成年的骨髓神经中，神经素可以诱导脱髓鞘，这有助于DPN。使用髓神经的细胞培养模型，我们已经确定葡萄糖会增加神经结合蛋白的退化作用。因此，这项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结合蛋白的表达和活性，并确定神经结合蛋白可以诱导神经变性的分子事件。这些研究的预期结果是，我们将确定可以增强生长因子在DPN治疗中的治疗益处的分子相互作用。