Effects of Semaphorin 3A on Stroke Recovery

Semaphorin 3A 对中风恢复的影响

基本信息

  • 批准号:
    8041869
  • 负责人:
  • 金额:
    $ 34.46万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2011
  • 资助国家:
    美国
  • 起止时间:
    2011-08-01 至 2014-05-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): After a stroke occurs, the brain up-regulates several repair pathways in an attempt to heal itself. One of the reasons for limited efficacy of this repair process lies in the presence of growth inhibitory factors in the injured region of the brain. Here, we propose to investigate the influence of signaling via the axon guidance molecule semaphorin 3A (Sema3A) on the recovery process after experimental stroke. Our hypothesis states that, analogous to its function in the developing brain, Sema3A acts as a repellent for growing axons and endothelial cells during adult neurogenesis and revascularization, and that this activity will be detrimental for the recovery process. Our pilot data suggest that i) Sema3A and its receptor neuropilin-1 (NRP-1), are up- regulated in the ischemic brain; ii) recombinant Sema3A leads to axon retraction in cultured cortical neurons, and inhibits tube formation in a brain endothelial cell line; and iii) Sema3A signaling can be disrupted by inhibition of 12/15-LOX. To expand these findings, we propose the following specific aims. In Aim 1, we use cultured primary neurons and a brain microvascular endothelial cell line to study the signaling pathways through which Sema3A operates. Both axonal pathfinding in neurons and development of new blood vessels following experimental stroke may be crucial for stroke recovery, and both are impacted by Sema3A. We will focus on signaling through the MAP kinase proteins, and on metabolites of 12/15-lipoxygenase, which have been shown to mediate the repulsive actions of Sema3A. In Aim 2, we study the expression of Sema3A and its receptor Neuropilin 1 (NRP1), in a mouse model of middle cerebral artery occlusion (MCAO). We will investigate differential effects of sema expression on neurogenesis-related axonal connectivity and the formation of brain microvessels, and correlate levels of Sema3A with functional recovery. In Aim 3, we inhibit axonal pathfinding of newly born neurons by injecting soluble semaphorin on the ipsilateral side of the brain subjected to MCAO. Alternatively, we disrupt semaphorin signaling by injecting an inhibitory peptoid, and by inhibiting the downstream mediator 12-lipoxygenase. Endogenous repair processes activated after stroke can potentially restore functionality to the damaged brain. Can manipulating the semaphorin pathway lead to more efficient integration of neurons and an improved revascularization? This application is relevant to PA-08-099 "Mechanisms of functional recovery after stroke". PUBLIC HEALTH RELEVANCE: Recovery from stroke could potentially benefit from endogenous repair processes, by which the injured brain tries to heal itself. Unfortunately, many challenges remain, because inhibitory molecules including semaphorin 3A (Sema3A) are detrimental to a successful rebuilding process. By investigating the molecular pathways by which Sema3A inhibits axon extension and the formation of new blood vessels, we hope to find treatment options to enhance the recovery process following stroke.
描述(由申请人提供):中风发生后,大脑上调几个修复途径,试图自我愈合。这种修复过程的功效有限的原因之一在于大脑受损区域中存在生长抑制因子。在这里,我们建议通过轴突导向分子semaphorin 3A(Sema 3A)对实验性中风后恢复过程中的信号传导的影响进行调查。我们的假设指出,类似于其在发育中的大脑中的功能,Sema 3A在成人神经发生和血管再生期间充当生长轴突和内皮细胞的排斥剂,并且这种活性将不利于恢复过程。我们的试验数据表明i)Sema 3A及其受体神经纤毛蛋白-1(NRP-1)在缺血性脑中上调; ii)重组Sema 3A导致培养的皮层神经元中的轴突回缩,并抑制脑内皮细胞系中的管形成;和iii)Sema 3A信号传导可通过抑制12/15-LOX而被破坏。为了扩大这些发现,我们提出了以下具体目标。在目的1中,我们使用培养的原代神经元和脑微血管内皮细胞系来研究Sema 3A通过其运作的信号通路。实验性中风后神经元中的轴突寻路和新血管的发育可能对中风恢复至关重要,两者都受到Sema 3A的影响。我们将专注于通过MAP激酶蛋白质的信号传导,以及12/15-脂氧合酶的代谢物,这些代谢物已被证明介导Sema 3A的排斥作用。目的二:研究Sema 3A及其受体神经纤毛蛋白1(Neuropilin 1,NRP 1)在小鼠大脑中动脉闭塞(MCAO)模型中的表达。我们将研究sema表达对神经发生相关轴突连接和脑微血管形成的不同影响,并将Sema 3A水平与功能恢复相关联。在目的3中,我们通过在MCAO的大脑同侧注射可溶性semaphorin来抑制新生神经元的轴突寻路。或者,我们通过注射抑制性类肽和抑制下游介体12-脂氧合酶来破坏脑信号蛋白信号传导。中风后激活的内源性修复过程可能会恢复受损大脑的功能。操纵脑信号蛋白通路能导致更有效的神经元整合和改善血管重建吗?本申请与PA-08-099“卒中后功能恢复机制”相关。 公共卫生相关性:从中风中恢复可能受益于内源性修复过程,通过该过程,受伤的大脑试图自我愈合。不幸的是,仍然存在许多挑战,因为包括semaphorin 3A(Sema 3A)在内的抑制性分子对成功的重建过程是有害的。通过研究Sema 3A抑制轴突延伸和新血管形成的分子途径,我们希望找到治疗方案,以加强中风后的恢复过程。

项目成果

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KLAUS VAN LEYEN其他文献

KLAUS VAN LEYEN的其他文献

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{{ truncateString('KLAUS VAN LEYEN', 18)}}的其他基金

A Novel Neuroprotectant to Reduce Ischemic Injury
一种减少缺血性损伤的新型神经保护剂
  • 批准号:
    10576568
  • 财政年份:
    2023
  • 资助金额:
    $ 34.46万
  • 项目类别:
Testing the Lipoxygenase Inhibitor BPN-27332 as Acute Phase Stroke Treatment in the SPAN Network
在 SPAN 网络中测试脂氧合酶抑制剂 BPN-27332 作为急性期中风治疗的作用
  • 批准号:
    10671991
  • 财政年份:
    2023
  • 资助金额:
    $ 34.46万
  • 项目类别:
Development of human 12/15-lipoxygenase therapeutics for stroke
开发人类 12/15-脂氧合酶治疗中风的药物
  • 批准号:
    9898504
  • 财政年份:
    2018
  • 资助金额:
    $ 34.46万
  • 项目类别:
Development of human 12/15-lipoxygenase therapeutics for stroke
开发人类 12/15-脂氧合酶治疗中风的药物
  • 批准号:
    9922389
  • 财政年份:
    2018
  • 资助金额:
    $ 34.46万
  • 项目类别:
Novel 12/15 lipoxygenase inhibitors for the treatment of stroke
用于治疗中风的新型 12/15 脂氧合酶抑制剂
  • 批准号:
    8684486
  • 财政年份:
    2014
  • 资助金额:
    $ 34.46万
  • 项目类别:
Novel 12/15 lipoxygenase inhibitors for the treatment of stroke
用于治疗中风的新型 12/15 脂氧合酶抑制剂
  • 批准号:
    8846695
  • 财政年份:
    2014
  • 资助金额:
    $ 34.46万
  • 项目类别:
Effects of Semaphorin 3A on Stroke Recovery
Semaphorin 3A 对中风恢复的影响
  • 批准号:
    8470260
  • 财政年份:
    2011
  • 资助金额:
    $ 34.46万
  • 项目类别:
Effects of Semaphorin 3A on Stroke Recovery
Semaphorin 3A 对中风恢复的影响
  • 批准号:
    8305479
  • 财政年份:
    2011
  • 资助金额:
    $ 34.46万
  • 项目类别:
12/15-Lipoxygenase and neurovascular damage following cardiac arrest
心脏骤停后的 12/15-脂氧合酶和神经血管损伤
  • 批准号:
    8239055
  • 财政年份:
    2005
  • 资助金额:
    $ 34.46万
  • 项目类别:
12/15-Lipoxygenase and neurovascular damage following cardiac arrest
心脏骤停后的 12/15-脂氧合酶和神经血管损伤
  • 批准号:
    8318072
  • 财政年份:
    2005
  • 资助金额:
    $ 34.46万
  • 项目类别:

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