An Animal Model of Diabetic Autonomic Neuropathy: Study of Mechanism and Therapy

糖尿病自主神经病变的动物模型:机制和治疗研究

基本信息

  • 批准号:
    7911877
  • 负责人:
  • 金额:
    $ 58.37万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2007
  • 资助国家:
    美国
  • 起止时间:
    2007-09-30 至 2012-08-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Diabetes mellitus is associated with severe debilitating complications which include a Diabetic Autonomic Neuropathy (DAN) characterized by decreased autonomic responsiveness of the heart. Approximately 50% of patients with diabetes for 10 years or more demonstrate DAN. Type I diabetics with evidence of DAN demonstrate a fivefold higher 5 year mortality and increased incidence of sudden death than those without DAN. Parasympathetic stimulation has been shown to protect the heart from the development of arrhythmias especially in the setting of myocardial infarction. Thus the increased incidence of sudden death in the diabetic population might reflect a predisposition to fatal arrhythmias in the presence of parasympathetic dysfunction. Parasympathetic response of the heart involves the interaction of the M2 muscarinic receptor, Gai2, and the inward rectifying K channel, (GIRK1)2/(Girk4)2 which stimulates IKACh and a decrease in beat rate and Gai2 and adenlyate cyclase which decreases the force of contraction. Insulin regulates levels of sterol response element binding proteins (SREBPs), which play a role in the control of cholesterol, fatty acid, and glucose metabolism. Preliminary data suggest that compared to non-diabetic WT, the type I diabetic Akita mouse demonstrates a decreased response to parasympathetic signaling and develops life threatening arrhythmias following myocardial infarction which are reversed by the muscarinic agonist carbamylcholine. Using this mouse 4 hypotheses will be tested: 1)that the Akita mouse is a model for DAN; demonstrates parasympathetic dysfunction, decreased IKACh decreased inhibition of 3-adrenergic stimulation of the heart 2) that hypoinsulinemia in diabetes results in a decrease in the expression of M2, Gai2, and GIRK1 in response to a decrease in SREBP 3) that the Type I diabetic Akita mouse is an animal model for the development of spontaneous life threatening arrhythmias following Ml and that parasympathetic dysfunction of DAN predisposes the heart to the development of arrhythmias and 4) that therapeutic interventions that increase SREBP such as insulin therapy or HMG-CoA reductase inhibitors increase M2, Gai2, and GIRK1 expression, reverse parasympathetic dysfunction and decrease the incidence of post Ml VT. This model offers a unique opportunity for new insights into mechanism and therapy of DAN and its relationship to arrhythmia and sudden death.
描述(由申请人提供):糖尿病与严重衰弱并发症相关,包括糖尿病自主神经病变(DAN),其特征为心脏自主反应性降低。大约50%的糖尿病患者10年或更长时间表现为DAN。有DAN证据的I型糖尿病患者的5年死亡率和猝死发生率比无DAN者高5倍。副交感神经刺激已被证明可以保护心脏免受心律失常的发展,特别是在心肌梗死的情况下。因此,糖尿病人群中猝死发生率的增加可能反映了副交感神经功能障碍时致命性心律失常的易感性。心脏的副交感神经反应涉及M2毒蕈碱受体Gai 2和内向整流K通道(GIRK 1)2/(Girk 4)2的相互作用,其刺激IKACh和心跳率的降低,以及Gai 2和腺苷酸环化酶的相互作用,其降低收缩力。胰岛素调节固醇反应元件结合蛋白(SREBP)的水平,其在控制胆固醇、脂肪酸和葡萄糖代谢中起作用。初步数据表明,与非糖尿病WT相比,I型糖尿病秋田小鼠表现出对副交感神经信号传导的反应降低,并在心肌梗死后发展出危及生命的心律失常,其被毒蕈碱激动剂氨甲酰胆碱逆转。使用该小鼠将检验4个假设:1)秋田小鼠是DAN的模型;表明副交感神经功能障碍,IKACh降低降低对心脏β-肾上腺素能刺激的抑制2)糖尿病中的低胰岛素血症导致M2,Gai 2,和GIRK 1对SREBP降低的反应3)I型糖尿病秋田小鼠是MI后发生自发性危及生命的心律失常的动物模型,4)增加SREBP的治疗性干预,如胰岛素疗法或HMG-CoA还原酶抑制剂增加M2、Gai 2和GIRK 1表达,逆转副交感神经功能障碍并降低MI后VT的发生率。该模型为深入了解DAN的机制和治疗及其与心律失常和猝死的关系提供了独特的机会。

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Jonas Bernard Galper其他文献

Jonas Bernard Galper的其他文献

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{{ truncateString('Jonas Bernard Galper', 18)}}的其他基金

A Role of PKG1a and Inhibitors of cGMP Phosphodiesterase in Post MI VT in Mouse Models for Type II Diabetes and Metabolic Syndrome
PKG1a 和 cGMP 磷酸二酯酶抑制剂在 II 型糖尿病和代谢综合征小鼠模型 MI 后 VT 中的作用
  • 批准号:
    10207769
  • 财政年份:
    2020
  • 资助金额:
    $ 58.37万
  • 项目类别:
A Role of PKG1a and Inhibitors of cGMP Phosphodiesterase in Post MI VT in Mouse Models for Type II Diabetes and Metabolic Syndrome
PKG1a 和 cGMP 磷酸二酯酶抑制剂在 II 型糖尿病和代谢综合征小鼠模型 MI 后 VT 中的作用
  • 批准号:
    10035716
  • 财政年份:
    2020
  • 资助金额:
    $ 58.37万
  • 项目类别:
A Role of PKG1a and Inhibitors of cGMP Phosphodiesterase in Post MI VT in Mouse Models for Type II Diabetes and Metabolic Syndrome
PKG1a 和 cGMP 磷酸二酯酶抑制剂在 II 型糖尿病和代谢综合征小鼠模型 MI 后 VT 中的作用
  • 批准号:
    10443778
  • 财政年份:
    2020
  • 资助金额:
    $ 58.37万
  • 项目类别:
A Role of PKG1a and Inhibitors of cGMP Phosphodiesterase in Post MI VT in Mouse Models for Type II Diabetes and Metabolic Syndrome
PKG1a 和 cGMP 磷酸二酯酶抑制剂在 II 型糖尿病和代谢综合征小鼠模型 MI 后 VT 中的作用
  • 批准号:
    10670741
  • 财政年份:
    2020
  • 资助金额:
    $ 58.37万
  • 项目类别:
Gender Specific Complications of Diabetic Autonomic Neuropathy: A New Mouse Model
糖尿病自主神经病变的性别特异性并发症:一种新的小鼠模型
  • 批准号:
    7923989
  • 财政年份:
    2009
  • 资助金额:
    $ 58.37万
  • 项目类别:
Gender Specific Complications of Diabetic Autonomic Neuropathy: A New Mouse Model
糖尿病自主神经病变的性别特异性并发症:一种新的小鼠模型
  • 批准号:
    7741155
  • 财政年份:
    2009
  • 资助金额:
    $ 58.37万
  • 项目类别:
An Animal Model of Diabetic Autonomic Neuropathy: Study of Mechanism and Therapy
糖尿病自主神经病变的动物模型:机制和治疗研究
  • 批准号:
    7316218
  • 财政年份:
    2007
  • 资助金额:
    $ 58.37万
  • 项目类别:
An Animal Model of Diabetic Autonomic Neuropathy: Study of Mechanism and Therapy
糖尿病自主神经病变的动物模型:机制和治疗研究
  • 批准号:
    7501466
  • 财政年份:
    2007
  • 资助金额:
    $ 58.37万
  • 项目类别:
An Animal Model of Diabetic Autonomic Neuropathy: Study of Mechanism and Therapy
糖尿病自主神经病变的动物模型:机制和治疗研究
  • 批准号:
    7681627
  • 财政年份:
    2007
  • 资助金额:
    $ 58.37万
  • 项目类别:
Role of Sterols and Insulin in Cardiac Autonomic Response
甾醇和胰岛素在心脏自主反应中的作用
  • 批准号:
    8098062
  • 财政年份:
    2004
  • 资助金额:
    $ 58.37万
  • 项目类别:

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能量代谢的神经内分泌调节:垂体腺苷酸环化酶激活多肽(PACAP)在温度调节级联中的作用
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