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

基本信息

  • 批准号:
    10558457
  • 负责人:
  • 金额:
    $ 34.77万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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 We have recently generated four unpublished mouse models with mutations in Ighmbp2 that correlate to mutations within the SMARD1 patient population.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.
摘要

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Christian L. Lorson其他文献

253. AAV Delivery of a Trans-Splicing RNA Re-Directs SMN2 Splicing and Results in Increased Full-Length SMN
  • DOI:
    10.1016/j.ymthe.2006.08.280
  • 发表时间:
    2006-01-01
  • 期刊:
  • 影响因子:
  • 作者:
    Tristan H. Coady;Monir Shababi;Christian L. Lorson
  • 通讯作者:
    Christian L. Lorson
415. Stimulating Full-Length SMN2 Expression by Delivering Bi-Functional RNAs Via a Viral Vector
  • DOI:
    10.1016/j.ymthe.2006.08.479
  • 发表时间:
    2006-01-01
  • 期刊:
  • 影响因子:
  • 作者:
    Travis D. Baughan;Monir Shababi;Gregory E. Tullis;Christian L. Lorson
  • 通讯作者:
    Christian L. Lorson
<em>Ighmbp2</em> mutations and disease pathology: Defining differences that differentiate SMARD1 and CMT2S
  • DOI:
    10.1016/j.expneurol.2024.115025
  • 发表时间:
    2025-01-01
  • 期刊:
  • 影响因子:
  • 作者:
    Sara M. Ricardez Hernandez;Bassil Ahmed;Yaser Al Rawi;F. Javier Llorente Torres;Mona O. Garro Kacher;Catherine L. Smith;Zayd Al Rawi;Jessica Garcia;Nicole L. Nichols;Christian L. Lorson;Monique A. Lorson
  • 通讯作者:
    Monique A. Lorson

Christian L. Lorson的其他文献

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{{ truncateString('Christian L. Lorson', 18)}}的其他基金

Improvements to the Regional Biocontainment Research Facilities at the University of Missouri
密苏里大学区域生物防护研究设施的改进
  • 批准号:
    10394455
  • 财政年份:
    2021
  • 资助金额:
    $ 34.77万
  • 项目类别:
Improvements to the Regional Biocontainment Research Facilities at the University of Missouri
密苏里大学区域生物防护研究设施的改进
  • 批准号:
    10631453
  • 财政年份:
    2021
  • 资助金额:
    $ 34.77万
  • 项目类别:
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
  • 财政年份:
    2020
  • 资助金额:
    $ 34.77万
  • 项目类别:
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
  • 财政年份:
    2020
  • 资助金额:
    $ 34.77万
  • 项目类别:
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:
    9973984
  • 财政年份:
    2020
  • 资助金额:
    $ 34.77万
  • 项目类别:
Evaluating AAV-mediated gene replacement for Spinal Muscular Atrophy with Respiratory Distress 1
评估 AAV 介导的基因替换对伴有呼吸窘迫的脊髓性肌萎缩症 1
  • 批准号:
    9034843
  • 财政年份:
    2015
  • 资助金额:
    $ 34.77万
  • 项目类别:
Monoallelic repair of expanded huntingtin by trans-splicing
通过反式剪接对扩展的亨廷顿蛋白进行单等位基因修复
  • 批准号:
    8048355
  • 财政年份:
    2010
  • 资助金额:
    $ 34.77万
  • 项目类别:
Monoallelic repair of expanded huntingtin by trans-splicing
通过反式剪接对扩展的亨廷顿蛋白进行单等位基因修复
  • 批准号:
    8129437
  • 财政年份:
    2010
  • 资助金额:
    $ 34.77万
  • 项目类别:
Funding for FightSMA Researchers' Conference in Washington, DC, April 2008
为 2008 年 4 月在华盛顿特区举行的 FightSMA 研究人员会议提供资金
  • 批准号:
    7487724
  • 财政年份:
    2008
  • 资助金额:
    $ 34.77万
  • 项目类别:
Stimulating SMN2 exon 7 inclusion with short RNAs
用短 RNA 刺激 SMN2 外显子 7 包含
  • 批准号:
    7945390
  • 财政年份:
    2007
  • 资助金额:
    $ 34.77万
  • 项目类别:

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