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: 10333249
• 负责人: Christian L. Lorson
• 金额: $ 34.77万
• 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/10333249
• 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; Persons; 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，他们失去了与下游肌肉靶标进行交流的能力，作为一个 结果，肌肉微弱，通常导致瘫痪和死亡。这种共同点在诸如罕见疾病（例如 脊柱肌肉萎缩，肌萎缩性侧性硬化症和呼吸遇险I型的SMA（SMARD1）。 总体上“罕见”的疾病非常普遍，仅在美国就会遭受约3000万人的困扰。理解 这些不同疾病之间的共座不仅利用特定于疾病的研究，而且还提供 利用共同的生化途径进行热发育的机会。以此为背景，这个项目 重点关注IGHMBP2基因，当突变会导致严重的运动神经元退行性疾病Smard1。 在CMT2（Charcot-Marie-type2）患者的一部分中也发现了IGHMBP2中的突变。 IGHMBP2是一个 普遍表达的蛋白质具有解旋酶功能，并提出了在RNA调节或RNA代谢中的作用。 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 月份。 SMARD1的患病率约为早期SMA患者的1％。 Smard1最初以不同的特征 下肢肌肉萎缩后来有近端肌肉无力。第一个主要的SMARD1临床症状，呼吸道 并发症，是由于diaphragmmantic瘫痪。我们最近生成了四个未发表的鼠标模型 在IGHMBP2中，与SMARD1患者人群中的突变相关。该项目的目的是表征 具有IGHMBP2突变C495X和D564N的两个新模型。 C495X与患者C496X突变有关 是在SMARD1中鉴定出的最普遍的IGHMBP2突变，并且在某些CMT2患者中也发现。发现C495X 作为纯合性隐性突变，作为患者的化合物杂合突变，并伴有呼吸道 遇险和运动神经元的缺陷早在几天和几年内就会出现。 D564N与患者D565N突变和 仅被鉴定为具有临床症状的复合杂合突变 年龄。 D565N蛋白结合核酸，具有ATPase活性，但缺乏解旋酶活性。 目标I中的实验旨在解决：疾病发作，疾病严重程度以及这种类型之间的关系 突变和SMARD1症状。在AIM II中，我们将检查分子和细胞表型，包括RNA和 蛋白质表达，运动神经元和肌肉分析以及呼吸功能。这些数据将与研究 已经检查了NMD鼠标（当前唯一可用的SMARD1模型）和SMA和ALS模型。 AIM III会 地址翻译的方法。这些研究应提供有关IGHMBP2在细胞中的作用的重要信息 流程和SMARD1开发。此外，这些研究应提供更大的知识基础以促进 治疗发展以及对相关神经疾病之间的相似性和差异的更好理解 更彻底地解决治疗发展。