NGF and RAGE-p75NTR signaling in models of amyotrophic lateral sclerosis

肌萎缩侧索硬化症模型中的 NGF 和 RAGE-p75NTR 信号传导

基本信息

批准号：
10058850
负责人：
Mariana Atina Pehar
金额：
$ 32.7万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-03-15 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10058850
关键词：
ALS pathology ALS patients Adaptor Signaling Protein Adopted Adult Amyotrophic Lateral Sclerosis Animal Model Apoptosis Apoptotic Astrocytes Birth Brain Stem Cell Culture Techniques Cell Death Cell Death Induction Cell Death Signaling Process Cessation of life Cleaved cell Clinical Complex Data Development Disease Disease Progression Environment Extracellular Domain Family Family member Gene Mutation Goals In Vitro Inherited Ligands Link Maintenance Mediating Modeling Modification Motor Cortex Motor Neuron Disease Motor Neurons Movement Mus NGFR Protein Nerve Degeneration Nerve Growth Factors Nervous system structure Neuraxis Neuroglia Neuronal Plasticity Neurons Neurotrophic Tyrosine Kinase Receptor Type 1 Neurotrophin 3 Paralysed Pathogenicity Pathologic Pathology Patients Phenotype Physiological Play Population Post-Translational Protein Processing Process Production Proteins Receptor Protein-Tyrosine Kinases Regulation Role Signal Pathway Signal Transduction Skeletal Muscle Spinal Cord Spinal Cord Diseases Stress Symptoms Tropomyosin Urine Work familial amyotrophic lateral sclerosis glycation in vivo insight member motor neuron degeneration mouse model neuron loss neurotrophic factor nitration novel overexpression potential biomarker receptor receptor for advanced glycation endproducts sortilin targeted treatment therapeutic target

项目摘要

Abstract Neurotrophins are essential for differentiation and survival of neurons during development and modulate neuronal plasticity in the adult nervous system. Nerve growth factor (NGF), the best-characterized member of the family, exerts its actions by signaling mainly through two transmembrane receptors, the tyrosine kinase receptor TrkA and the p75 neurotrophin receptor (p75NTR). Besides promoting survival, NGF can also induce cell death by signaling through p75NTR. p75NTR is re-expressed at high levels by stressed neurons in pathological conditions, including amyotrophic lateral sclerosis (ALS). ALS is the most common adult onset motor neuron disease, characterized by the progressive degeneration of upper and lower motor neurons, leading to paralysis and death one to five years after symptoms onset. We have shown that in an ALS-mouse model, the re-expression of p75NTR by motor neurons coincides with an increase production of NGF by reactive astrocytes. However, the ability of mature NGF to induce cell death has been challenged because high concentrations of the neurotrophin are required to induce cell death in vitro, at least an order of magnitude higher than the required to promote survival. More than ten years ago, pro-neurotrophins were identified as the pro-apoptotic ligands of p75NTR, able to induce cell death at subnanomolar concentrations. Since then, pro- neurotrophins are considered the physiologically relevant pro-apoptotic ligands of p75NTR, and the field has focused on the regulation of pro-neurotrophin processing as the switch regulating the pro-survival/pro-death signaling of neurotrophins. Our proposal challenges this paradigm and adds a new layer of complexity. It shows that the pro-survival/pro-death activity of NGF could also be regulated by post-translational modification of the mature neurotrophin. Our preliminary data indicate that nitration and glycation confer mature NGF the exceptional ability to induce cell death at physiologically relevant concentrations (10,000-fold less compared to that required by native NGF). In addition, it identified RAGE, the receptor for advance glycation end products, as a new partner of p75NTR in the induction of cell death by post-translational modified-mature NGF. The primary goal of this proposal is to identify the mechanism by which post-translational modifications confer upon NGF the ability to signal through p75NTR and RAGE to promote cell death, and to establish its pathophysiological relevance in models of ALS. We will focus on the following specific aims: Aim 1-To identify the signaling pathways activated by post-translational modified-NGF. Aim 2-To elucidate the role of post- translational modified-NGF signaling in ALS cell culture models. Aim 3-To evaluate the effect of inhibiting RAGE-p75NTR signaling on the progression of the disease in ALS mouse models. This proposal will contribute to the current understanding of neurotrophin-mediated death signaling and it will provide in vitro evidence for the involvement of RAGE-p75NTR signaling in ALS pathology. Finally, it will provide in vivo proof for the role of RAGE signaling in astrocytes versus motor neurons and its value as a therapeutic target in ALS.

抽象的神经营养蛋白对于在发育和调节过程中神经元的分化和存活至关重要成人神经系统中的神经元可塑性。神经生长因子（NGF），是特征最佳的成员该家族通过主要通过两个跨膜受体（酪氨酸激酶）发出信号来发挥作用受体TRKA和p75神经营养蛋白受体（P75NTR）。除了促进生存外，NGF还可以诱导通过P75NTR信号传导通过信号死亡。 P75NTR在高水平的高水平上被压力神经元重新表达病理状况，包括肌萎缩性侧索硬化症（ALS）。 ALS是最常见的成人发作运动神经元疾病，其特征是上和下运动神经元的进行性变性，症状发作后一到五年导致瘫痪和死亡。我们已经在ALS-Mouse中表明模型，运动神经元对P75NTR的重新表达与反应性增加NGF的产生星形胶质细胞。但是，成熟的NGF诱导细胞死亡的能力受到挑战，因为高需要神经营养蛋白的浓度在体外诱导细胞死亡，至少是一个数量级高于促进生存所需的要求。十多年前，亲毒素被确定为 P75NTR的促凋亡配体，能够在亚菜单浓度下诱导细胞死亡。从那以后，Pro- 神经营养蛋白被认为是p75ntr的生理相关的促凋亡配体侧重于调节促尿营养蛋白处理，以调节促卵巢/亲死亡的开关神经营养蛋白的信号传导。我们的建议挑战了这一范式，并增加了新的复杂性。它表明NGF的亲阳性/促生气活动也可以通过翻译后修饰来调节成熟的神经营养蛋白。我们的初步数据表明，硝化和糖基授予成熟的NGF 在生理相关浓度下诱导细胞死亡的特殊能力（与本机NGF所要求的）。此外，它确定了愤怒，即预先糖基化终产物的受体，作为P75NTR的新合作伙伴，通过翻译后的成熟NGF诱导细胞死亡。这该提案的主要目标是确定翻译后修改的机制 NGF通过p75ntr和愤怒发出信号的能力促进细胞死亡，并确定其 ALS模型中的病理生理相关性。我们将重点介绍以下特定目标：目标1识别信号通路被翻译后修饰的NGF激活。瞄准2阐明后的作用 ALS细胞培养模型中的翻译修饰-NGF信号传导。目标3来评估抑制的效果 ALS小鼠模型中疾病进展的RAGE-P75NTR信号传导。该提议将做出贡献为了当前对神经营养蛋白介导的死亡信号传导的理解，它将提供体外证据 RAGE-P75NTR信号在ALS病理学中的参与。最后，它将为体内证明作用星形胶质细胞与运动神经元中的愤怒信号传导及其作为ALS治疗靶标的值。