Novel SMARD1 Mouse Models: Characterization and Evaluation of Potential Therapeutic Targets

新型 SMARD1 小鼠模型：潜在治疗靶点的表征和评估

• 批准号: 10087982
• 负责人: Christian L. Lorson
• 金额: $ 34.72万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10087982
• 关键词: ATP phosphohydrolase; Address; Adolescent; Affect; Age-Months; Amyotrophic Lateral Sclerosis; Binding; Biochemical; Biochemical Pathway; Biochemistry; Biological; Biological Assay; Cell physiology; Cessation of life; Charcot-Marie-Tooth Disease; Child; Chimera organism; Clinical; Complication; Cultured Cells; DNA; DNA Binding; Data; Defect; Degenerative Disorder; Development; Disease; Disease model; Distal; Electrophysiology (science); Evaluation; Genes; Genetic Transcription; Hand Strength; Hereditary Motor and Sensory-Neuropathy Type II; Hindlimb; Lead; Life Expectancy; Longevity; Lower Extremity; Mind; Missense Mutation; Modeling; Molecular; Motor Neuron Disease; Motor Neurons; Mus; Muscle; Muscle Weakness; Muscular Atrophy; Mutant Strains Mice; Mutate; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Nucleic Acid Binding; Onset of illness; Paralysed; Pathway interactions; Patients; Phenotype; Prevalence; Proteins; Public Health; RNA; RNA Binding; RNA metabolism; Ramp; Rare Diseases; Regulation; Research; Resistance; Resources; Respiratory Paralysis; Respiratory distress; Respiratory physiology; Role; Series; Severity of illness; Spinal Muscular Atrophy; Symptoms; Time; Transgenic Organisms; Tyrosine-Specific tRNA; United States; Weight; base; cell type; design; early onset; effective therapy; experimental study; gene function; gene product; gene replacement; helicase; improved; knowledge base; mouse model; mutant; nervous system disorder; neuromuscular; novel; nucleic acid binding protein; patient population; protein B; protein expression; residence; respiratory; therapeutic development; therapeutic target; therapeutically effective; tool; translational approach

Abstract When motor neurons degenerate, they lose their ability to communicate with their downstream muscle targets and, as a result, muscles weaken, often leading to paralysis and death. This commonality is shared between rare diseases such as Spinal Muscular Atrophy, Amyotrophic Lateral Sclerosis, and SMA with Respiratory Distress Type I (SMARD1). Collectively “rare” disorders are strikingly common, afflicting ~30 million people in the United States alone. Understanding commonalties between these different conditions not only leverages disease-specific research but also provides opportunities to exploit shared biochemical pathways for therapeutic development. With this as a backdrop, this project focuses on the IGHMBP2 gene, that when mutated results in a severe motor neuron degenerative disease, SMARD1; mutations in IGHMBP2 are also found in a subset of CMT2 (Charcot-Marie-Tooth Type2) patients. IGHMBP2 is a ubiquitously expressed protein with helicase function and proposed roles in RNA regulation or RNA metabolism. SMARD1 is an autosomal recessive motor neuron disease that primarily affects children, with a life expectancy of ~13 months. The prevalence of SMARD1 is ~1 percent of early onset SMA patients. SMARD1 is initially characterized by distal lower limb muscle atrophy with proximal muscle weakness later. The first major SMARD1 clinical symptom, respiratory complication, is due to diaphragmatic paralysis. We have recently generated four unpublished mouse models with mutations in Ighmbp2 that correlate to mutations within the SMARD1 patient population. The objective of this project is to characterize two of the new models with Ighmbp2 mutations C495X and D564N. C495X correlates to the patient C496X mutation that is the most prevalent IGHMBP2 mutation identified in SMARD1 and is also found in some CMT2 patients. C495X is found as a homozygous recessive mutation and as a compound heterozygous mutation in patients and presents with respiratory distress and motor neuron defects as early as days and as late as years. D564N correlates to the patient D565N mutation and has only been identified as a compound heterozygous mutation with clinical symptoms initiating as early as several months of age. D565N protein binds nucleic acid, has ATPase activity, but lacks helicase activity. Experiments in AIM I are designed to address: disease onset, disease severity, and the relationship between the type of mutation and SMARD1 symptoms. In AIM II we will examine the molecular and cellular phenotypes, including RNA and protein expression, motor neuron and muscle analyses, and respiratory function. These data will be compared to studies that have examined the nmd mouse (the only SMARD1 model currently available) and SMA and ALS models. AIM III will address translational approaches. These studies should provide significant information into the role of Ighmbp2 in cellular processes and SMARD1 development. Additionally, these studies should provide a greater knowledge base to facilitate therapeutic development and a better understanding of the similarities and differences between related neurological diseases to more completely address therapeutic development.

抽象的 当运动神经元退化时，它们会失去与下游肌肉目标沟通的能力，并且作为 结果，肌肉衰弱，常常导致瘫痪和死亡，这种共性是罕见疾病（例如，）所共有的。 脊髓性肌萎缩症、肌萎缩侧索硬化症和 I 型呼吸窘迫型 SMA (SMARD1)。 总体而言，“罕见”疾病非常常见，仅在美国就有约 3000 万人受到影响。 这些不同条件之间的共性不仅利用了针对特定疾病的研究，而且还提供了 以此为背景，该项目提供了利用共享生化途径进行治疗开发的机会。 重点关注 IGHMBP2 基因，该基因突变后会导致严重的运动神经元退行性疾病 SMARD1； IGHMBP2 突变也存在于 CMT2（Charcot-Marie-Tooth 2 型）患者亚群中。 普遍表达的具有解旋酶功能的蛋白质，并在 RNA 调节或 RNA 代谢中发挥作用。 SMARD1 是一种常染色体隐性运动神经元疾病，主要影响儿童，预期寿命约为 13 岁 早发 SMA 患者中 SMARD1 的患病率约为 1%，其最初特征是远端。 下肢肌肉萎缩，随后出现近端肌肉无力 第一个主要的 SMARD1 临床症状是呼吸系统。 并发症是由于膈肌麻痹引起的，我们最近生成了四种未发表的带有突变的小鼠模型。 Ighmbp2 中与 SMARD1 患者群体中的突变相关的该项目的目标是表征。 两个具有 Ighmbp2 突变 C495X 和 D564N 的新模型与患者 C496X 突变相关。 是 SMARD1 中最常见的 IGHMBP2 突变，也在一些 CMT2 患者中发现。 作为患者的纯合隐性突变和复合杂合突变，并表现为呼吸道疾病 早至数天、晚至数年的痛苦和运动神经元缺陷与患者 D565N 突变相关。 仅被鉴定为复合杂合突变，其临床症状早在几个月内就开始出现 D565N 蛋白结合核酸，具有 ATP 酶活性，但缺乏解旋酶活性。 AIM I 中的实验旨在解决：疾病发作、疾病严重程度以及疾病类型之间的关系。 在 AIM II 中，我们将检查分子和细胞表型，包括 RNA 和 SMARD1 症状。 这些数据将与研究进行比较。 已经检查了 nmd 鼠标（目前唯一可用的 SMARD1 型号）以及 SMA 和 ALS III 型号。 这些研究应该为 Ighmbp2 在细胞中的作用提供重要信息。 此外，这些研究应提供更大的知识基础以促进。 治疗方法的发展以及更好地了解相关神经系统疾病之间的异同 更全面地解决治疗发展问题。