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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

基本信息

批准号：
8206566
负责人：
Rick T Dobrowsky
金额：
$ 30.77万
依托单位：
UNIVERSITY OF KANSAS LAWRENCE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-02-01 至 2013-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8206566
关键词：
Address Adult Affect Afferent Neurons Animal Model Apoptosis Attention Axon Belief Binding Biological Assay Cell Count Cell Culture Techniques Cell Death Cell Nucleus Cell Survival Cell model Cells Cessation of life Coculture Techniques Collaborations Complex Coupled Data Demyelinations Diabetes Mellitus Diabetic Neuropathies Down-Regulation Doxycycline Electron Microscopy Embryo Esthesia Etiology Event Figs - dietary Fright Functional disorder Glucose Goals Growth Factor Health Hyperglycemia Image Impairment In Vitro Induction of Apoptosis Insulin-Like Growth Factor I Knock-out Knockout Mice Leg Literature Measurement Measures Mechanics Metric Modeling Molecular Motor Mus Myelin Nerve Nerve Degeneration Neural Conduction Neuregulin 1 Neuregulins Neuronal Dysfunction Neurons Neuropathy Outcome Study Pathologic Peripheral Nerves Peripheral Nervous System Diseases Preparation Principal Investigator Procedures Proteins Published Comment Reading Receptor Protein-Tyrosine Kinases Research Schwann Cells Sensory Serum Serum-Free Culture Media Signal Transduction Solid Staining method Stains Stimulation of Cell Proliferation Stress System Therapeutic Time Transgenic Mice Wild Type Mouse Work arm base caveolin 1 cellular microvillus diabetic ezrin immunoreactivity in vivo insight knockout animal light microscopy morphometry myelination novel programs research study response

项目摘要

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）的病因复杂，涉及神经元和雪旺细胞（SC）的变性。虽然很多注意力都集中在如何改变生长因子信号有助于神经元功能障碍，一个显着的差距存在于我们的理解如何hyper-binding影响胶质营养因子。神经调节蛋白-1（NRG 1）是一种神经胶质营养生长因子，其通过激活发育中的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，有髓鞘SC中Erb B2的病理性激活可诱导脱髓鞘和周围神经病变的发作。我们广泛的假设是糖尿病诱导了一种“改变的神经调节蛋白”，这种改变有助于SC变性和DPN的进展。为了支持这一假设，我们提供的证据表明，糖尿病刺激外周神经中的Erb B2活性，这与Erb B2的负调节因子小窝蛋白-1（Cav-1）的下调相关。使用有髓鞘SC/感觉神经元共培养物，我们证明高血糖症降低Cav-1水平并增强NRG 1诱导的脱髓鞘。Cav-1可能有助于体内有髓轴突的变性，因为糖尿病Cav-1敲除小鼠与野生型小鼠相比，机械性痛觉减退的发病率更快。同样，我们表明，Erb B2的活动是足以导致运动神经传导速度的下降，并诱导机械痛觉减退，使用一种新的SC特异性条件转基因小鼠，上调组成型活性Erb B2在响应多西环素。因此，我们的目标是整合动物和细胞模型的研究结果，以获得机制洞察Erb B2的病理激活如何影响SC，并有助于DPN感觉功能障碍的发作。我们的目标是：1）使用来自野生型和Cav-1缺失小鼠的有髓鞘SC/感觉神经元外植体确定Cav- 1在高血糖条件下增强NRG 1的变性作用的机制，2）使用Cav-1缺失小鼠确定Cav-1促进Erb B2活化和DPN发作的必要性/充分性，以及3）确定糖尿病对糖尿病神经中NRG表达的影响，并使用新的Erb B2条件转基因小鼠确定Erb B2在促成感觉缺陷方面的充分性。这项工作将提供一个新的范例，了解NRG在调节DPN的轴胶质细胞相互作用的影响。公共卫生相关性：糖尿病周围神经病变（DPN）是由腿部和手臂的感觉传递神经变性引起的。雪旺细胞（SC）是与许多神经密切相关的特化细胞，在DPN中也发生了深刻的变化。我们的假设是，长时间的高血糖应激改变了SC对称为神经调节素的生长因子的反应。在成年有髓神经中，神经调节蛋白可诱导脱髓鞘，这有助于DPN。使用有髓鞘神经的细胞培养模型，我们已经确定，葡萄糖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神经调节蛋白在小鼠糖尿病神经中的表达和活性，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治疗DPN的治疗益处的分子相互作用。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Hyperglycemia alters the schwann cell mitochondrial proteome and decreases coupled respiration in the absence of superoxide production.

DOI：
10.1021/pr900818g
发表时间：
2010-01
期刊：
JOURNAL OF PROTEOME RESEARCH
影响因子：
4.4
作者：
Zhang, Liang;Yu, Cuijuan;Vasquez, Francisco E.;Galeva, Nadya;Onyango, Isaac;Swerdlow, Russell H.;Dobrowsky, Rick T.
通讯作者：
Dobrowsky, Rick T.

Nutrient excess and altered mitochondrial proteome and function contribute to neurodegeneration in diabetes.