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.

抽象的神经营养素对于神经元发育和调节过程中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），最具特征的成员该家族主要通过两种跨膜受体（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 信号传导导致细胞死亡。 p75NTR 在受应激的神经元中以高水平重新表达病理状况，包括肌萎缩侧索硬化症（ALS）。 ALS 是最常见的成人发病运动神经元疾病，其特征是上运动神经元和下运动神经元进行性退化，症状出现后一到五年导致瘫痪和死亡。我们已经证明，在 ALS 小鼠中模型中，运动神经元重新表达 p75NTR 与反应性 NGF 产量增加同时发生。星形胶质细胞。然而，成熟的 NGF 诱导细胞死亡的能力受到了挑战，因为高体外诱导细胞死亡需要神经营养蛋白的浓度，至少一个数量级高于促进生存所需的水平。十多年前，前神经营养素被认为是 p75NTR 的促凋亡配体，能够在亚纳摩尔浓度下诱导细胞死亡。从此以后，亲神经营养素被认为是 p75NTR 生理相关的促凋亡配体，该领域已专注于前神经营养蛋白加工的调节作为调节促生存/促死亡的开关神经营养素的信号传导。我们的提案挑战了这种范式，并增加了新的复杂性。它表明 NGF 的促生存/促死亡活性也可以通过翻译后修饰来调节成熟的神经营养素。我们的初步数据表明，硝化和糖化赋予成熟的 NGF 在生理相关浓度下诱导细胞死亡的卓越能力（与传统浓度相比低 10,000 倍）天然 NGF 所需的）。此外，它还鉴定出 RAGE，高级糖基化终产物的受体，作为 p75NTR 的新伙伴，通过翻译后修饰的成熟 NGF 诱导细胞死亡。这该提案的主要目标是确定翻译后修饰赋予的机制 NGF 能够通过 p75NTR 和 RAGE 发出信号以促进细胞死亡，并建立其 ALS 模型中的病理生理学相关性。我们将重点关注以下具体目标：目标 1-确定由翻译后修饰的 NGF 激活的信号通路。目标 2-阐明后处理的作用 ALS 细胞培养模型中的翻译修饰 NGF 信号传导。目标3-评估抑制效果 RAGE-p75NTR 信号传导对 ALS 小鼠模型疾病进展的影响。该提案将有助于目前对神经营养蛋白介导的死亡信号传导的理解，它将为以下方面提供体外证据： RAGE-p75NTR 信号传导参与 ALS 病理学。最后，它将为其作用提供体内证据。星形胶质细胞与运动神经元中的 RAGE 信号传导及其作为 ALS 治疗靶点的价值。