The Role of p38 MAPK Activation in Spinal Muscular Atrophy

p38 MAPK 激活在脊髓性肌萎缩症中的作用

• 批准号: 9317946
• 负责人: Livio Pellizzoni
• 金额: $ 24万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9317946
• 关键词: Address; Animal Model; Behavior; Biology; Cause of Death; Cessation of life; Clinical Trials; Complement; Data; Denervation; Development; Disease; Event; Functional disorder; Future; Gene Delivery; Genetic; Genetic Screening; Inborn Genetic Diseases; Inherited; Knowledge; Link; MAP Kinase Gene; MAPK14 gene; Mammalian Cell; Mediating; Molecular; Morphology; Motor; Motor Neuron Disease; Motor Neurons; Mus; Muscle; Neurodegenerative Disorders; Neuromuscular Junction; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patients; Pharmacology; Phenotype; Phosphorylation; Process; RNA; RNA Interference; RNA Processing; Role; SMN protein (spinal muscular atrophy); Severity of illness; Spinal Cord; Spinal Muscular Atrophy; Synapses; System; TP53 gene; Testing; Therapeutic; Up-Regulation; cell type; cellular targeting; chemical genetics; design; effective therapy; experimental study; genetic approach; improved; in vivo; infancy; inhibitor/antagonist; insight; knock-down; longitudinal analysis; motor deficit; motor disorder; motor neuron degeneration; mouse model; neuromuscular; neuron loss; neurotransmission; novel; novel therapeutic intervention; preclinical study; skeletal muscle wasting; spinal pathway; success; therapeutic development; therapeutic target

Project Summary Spinal muscular atrophy (SMA) is an inherited neurodegenerative disease characterized by motor neuron loss and skeletal muscle atrophy. SMA is caused by ubiquitous deficiency in the survival motor neuron (SMN) protein and, given the well-established direct correlation between the degree of SMN reduction and disease severity, most SMA therapeutic approaches to date have focused on increasing the levels of SMN expression through multiple strategies. The remarkable success of several of these approaches in preclinical studies has led to ongoing clinical trials. However, no effective therapy is currently available for SMA, which remains the most common genetic cause of death in infancy. Therefore, there is an urgent need to identify treatments that can either restore SMN levels or correct the deficits downstream of SMN depletion in SMA patients. Furthermore, while greater knowledge of the central role of SMN in RNA processing combined with characterization of animal models of SMA have significantly advanced our understanding of the disease, the precise molecular and cellular events that underlie the dysfunction and death of SMA motor neurons remain elusive. Clearly, identification of cellular factors and pathways contributing to synaptic dysfunction and selective neuronal death induced by SMN deficiency is not only essential to understand disease mechanisms but may also broaden the range of targets for developing SMA therapies that can complement SMN upregulation approaches. This project aims to characterize a novel cellular pathway that is dysregulated in SMA in order to increase our understanding of the downstream events induced by SMN deficiency that are relevant to the disease process, which may also represent novel potential therapeutic targets. In a chemical genetic screen for agents that suppress cellular phenotypes induced by SMN deficiency in cultured mammalian cells, we identified p38MAPK inhibitors as candidate modifiers of SMN biology. Further studies revealed that SMN deficiency induces p38MAPK activation in vivo and its pharmacological inhibition improves motor deficits in SMA mice. Building on these findings, here we propose to determine the precise contribution of p38MAPK dysregulation to motor dysfunction using both pharmacological and genetic approaches in a mouse model of SMA. In Aim 1, we will perform a longitudinal analysis of the effects of inhibiting the p38MAPK pathway on morphological and functional abnormalities induced by SMN deficiency in the SMA motor system. In Aim 2, we will carry out a comprehensive set of studies to determine the p38MAPK-dependent molecular and cellular events that may contribute to SMA pathology, with a particular emphasis on the mechanisms of motor neuron degeneration. Collectively, these studies are designed to establish activation of the p38MAPK pathway as a key component of the pathogenic cascade induced by SMN deficiency during the disease process and to provide proof-of-concept for its inhibition as a novel, SMN-independent therapeutic approach for SMA.

项目摘要 脊髓性肌萎缩症是一种以运动神经元缺失为特征的遗传性神经退行性疾病 和骨骼肌萎缩。SMA是由生存运动神经元（SMN）的普遍缺陷引起的 考虑到SMN减少程度与疾病之间的明确直接相关性， 由于病情严重，迄今为止大多数SMA治疗方法都集中在增加SMN表达水平 通过多种策略。这些方法中的几种在临床前研究中取得了显着的成功， 进行了临床试验然而，SMA目前没有有效的治疗方法， 最常见的婴儿期死亡的遗传原因。因此，迫切需要确定 可以恢复SMA患者的SMN水平或纠正SMN耗竭下游的缺陷。 此外，虽然更多地了解SMN在RNA加工中的核心作用， SMA动物模型的表征显著地推进了我们对该疾病的理解， SMA运动神经元功能障碍和死亡的确切分子和细胞事件仍然存在 难以捉摸。很明显，识别导致突触功能障碍的细胞因子和途径， SMN缺乏诱导的选择性神经元死亡不仅对理解疾病机制至关重要， 但也可能扩大SMA治疗的靶点范围， 上调方法。该项目旨在描述一种新的细胞通路，该通路在细胞内失调， SMA，以增加我们对SMN缺乏引起的下游事件的理解， 与疾病过程相关，这也可能代表新的潜在治疗靶点。某化工 在培养的哺乳动物中抑制由SMN缺乏诱导的细胞表型的试剂的遗传筛选 细胞，我们确定p38 MAPK抑制剂作为候选的SMN生物学修饰剂。进一步的研究表明， SMN缺乏诱导体内p38 MAPK活化及其药理学抑制改善运动缺陷 SMA小鼠。在这些发现的基础上，我们建议确定p38 MAPK的精确贡献 使用药理学和遗传学方法在小鼠模型中研究了运动功能障碍的调节异常。 SMA。在目的1中，我们将对抑制p38 MAPK通路对细胞凋亡的影响进行纵向分析。 SMA运动系统中SMN缺陷引起的形态和功能异常。在目标2中， 将进行一系列全面的研究，以确定p38MAPK依赖的分子和细胞 可能导致SMA病理学的事件，特别强调运动神经元的机制 退化总的来说，这些研究旨在建立p38 MAPK通路的激活作为一种抑制肿瘤细胞增殖的机制。 疾病过程中SMN缺乏诱导的致病级联反应的关键组分， 作为SMA的一种新型SMN非依赖性治疗方法，提供了其抑制作用的概念验证。