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12/15-Lipoxygenase and Diabetic Neuropathy

12/15-Lipoxygenase and Diabetic Neuropathy
12/15-脂氧合酶和糖尿病神经病变
批准号:
8085917
负责人:
IRINA G OBROSOVA
金额:
$29.07万
依托单位国家:
美国
项目类别:
财政年份:
2007
资助国家:
美国
项目状态:
已结题
起止时间:
2007-09-01 至 2013-01-31

项目摘要

项目成果

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中文摘要
翻译
描述(由申请人提供):花生四烯酸代谢在糖尿病并发症中的重要作用的证据正在出现。最近的体内和细胞培养研究,包括我们小组的研究,揭示了12/15-脂氧合酶(12/15-LO)1)有助于受损的细胞信号传导和炎症反应;和2)涉及与糖尿病相关的内皮功能障碍,肾病和视网膜病变的发病机制。本提案的目的是使用1型和2型糖尿病的动物模型以及小鼠雪旺细胞和DRG神经元的高糖暴露共培养物和人雪旺细胞(HSC)培养物来评估12/15-LO在周围糖尿病神经病变(PDN)中的作用。我们的初步数据表明:1)12/15-LO在周围神经中大量表达,并且其表达和活性在糖尿病条件下增加; 2)12/15-LO-/-小鼠比野生型小鼠发展更轻的PDN; 3)STZ-糖尿病小鼠中的PDN的一些表现被短期12/15-LO抑制剂治疗逆转; 4)在HSC短期(24小时)暴露于高糖后,12/15-LO过表达是明显的;和5)12/15-LO抑制剂治疗抵消HSC中高糖诱导的促分裂原活化蛋白激酶(MAPK)磷酸化。具体目的是:1)评价两种结构上不相关的12/15-LO抑制剂对1型和2型糖尿病小鼠模型中PDN的功能、生化和结构指数的影响,即,2)比较患有1型和2型糖尿病的12/15-LO-/-小鼠和野生型小鼠中PDN的严重程度; 3)评估PDN的最重要的“上游”机制,即增加的醛糖还原酶活性在12/15-LO上调中的作用,和4)检查12/15-LO对MAPK活化的贡献,在上述动物和细胞培养模型中的外周神经、脊髓和DRG神经元中。该项目将结合联合收割机的生理,行为,生物化学,免疫组织化学和结构的研究与生物化学(HPLC,蛋白质印迹,荧光分光光度酶测定)和分子(实时PCR,siRNA转染)的方法在细胞培养模型的动物。这些发现将产生关于12/15-LO在1型和2型糖尿病PDN中作用的新信息,并可能为开发12/15-LO抑制剂以预防和治疗糖尿病提供理论基础。
英文摘要
DESCRIPTION (provided by applicant): Evidence for the important role of arachidonic acid metabolism in diabetes complications is emerging. Recent in vivo and cell culture studies including those from our group revealed that 12/15-lipoxygenase (12/15-LO) 1) contributes to impaired cell signaling and inflammatory response; and 2) is implicated in the pathogenesis of endothelial dysfunction, nephropathy and retinopathy, associated with diabetes. The objective of this proposal is to evaluate the role of 12/15-LO in peripheral diabetic neuropathy (PDN) using animal models of Type 1 and Type 2 diabetes and high glucose-exposed co-cultures of mouse Schwann cells and DRG neurons and cultures of human Schwann cells (HSC). Our preliminary data indicate that 1) 12/15-LO is abundantly expressed in the peripheral nerve and its expression and activity increase in diabetic conditions; 2) 12/15-LO-/- mice develop less severe PDN than wild-type mice; 3) some manifestations of PDN in STZ-diabetic mice are reversed by a short-term 12/15-LO inhibitor treatment; 4) 12/15-LO overexpression is manifest after a short-term (24h) exposure of HSC to high glucose; and 5) a 12/15-LO inhibitor treatment counteracts high glucose-induced mitogen-activated protein kinase (MAPK) phosphorylation in HSC. The SPECIFIC AIMS are 1) evaluate two structurally unrelated 12/15-LO inhibitors on functional, biochemical and structural indices of PDN in mouse models of Type 1 and Type 2 diabetes, i.e., STZ-diabetic and high-fat diet fed mice; 2) compare severity of PDN in 12/15-LO-/- mice and wild-type mice with Type 1 and Type 2 diabetes; 3) assess the role for the most important, "upstream", mechanism of PDN, i.e. increased aldose reductase activity, in 12/15-LO upregulation, and 4) examine the contribution of 12/15-LO to MAPK activation, in peripheral nerve, spinal cord and DRG neurons in the afore-mentioned animal and cell culture models. The project will combine physiological, behavioral, biochemical, immunohistochemical and structural studies in animals with biochemical (HPLC, Western blotting, spectrofluorometric enzymatic assays) and molecular (real-time PCR, siRNA transfections) approaches in cell culture models. The findings will generate new information on the role for 12/15-LO in PDN of Type 1 and Type 2 diabetes, and may provide rationale for development of 12/15-LO inhibitors for its prevention and treatment.
期刊论文(3)
专著(0)
科研奖励(0)
会议论文
DOI: 10.1016/j.bcp.2009.11.018
发表时间: 2010-04-01
期刊: BIOCHEMICAL PHARMACOLOGY
影响因子: 5.8
作者: [Shevalye, Hanna, Stavniichuk, Roman, Xu, Weizheng, Zhang, Jie, Lupachyk, Sergey, Maksimchyk, Yury, Drel, Viktor R., Floyd, Elizabeth Z., Slusher, Barbara, Obrosova, Irina G.]
通讯作者: Obrosova, Irina G.
DOI: 10.3892/ijmm_00000445
发表时间: 2010-07
期刊: International journal of molecular medicine
影响因子: 5.4
作者: [Obrosova IG, Maksimchyk Y, Pacher P, Agardh E, Smith ML, El-Remessy AB, Agardh CD]
通讯作者: Agardh CD
Peroxynitrite, protein nitration and advanced diabetic neuropathy
Peroxynitrite, protein nitration and advanced diabetic neuropathy
Peroxynitrite, protein nitration and advanced diabetic neuropathy
Na+/H+-exchanger-1 and Diabetic Neuropathy
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  • 项目类别:
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  • 资助金额:
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  • 批准年份:
    2020
  • 负责人:
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  • 依托单位:
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  • 批准号:
    21172061
  • 项目类别:
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  • 资助金额:
    30.0万元
  • 批准年份:
    2011
  • 负责人:
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  • 依托单位: