SMN associated proteins and compounds for SMA therapy

用于 SMA 治疗的 SMN 相关蛋白和化合物

• 批准号: 6900972
• 负责人: JIANHUA ZHOU
• 金额: $ 27.24万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-01 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6900972
• 关键词: DNA binding protein; RNA splicing; beta lactamase; biological signal transduction; degenerative motor system disease; disease /disorder model; gene deletion mutation; gene expression; genetically modified animals; green fluorescent proteins; immunoprecipitation; laboratory mouse; laboratory rabbit; messenger RNA; microarray technology; motor neurons; neuropharmacology; pathologic process; phosphatase inhibitor; progressive spinal muscular atrophy; protein structure function; small nuclear ribonucleoproteins; telomere; tissue /cell culture; yeast two hybrid system

DESCRIPTION (provided by applicant): The autosomal recessive spinal muscular atrophy (SMA) is one of the most common genetic causes of infant death. In SMA, there is anterior horn cell death and muscle weakness. Deletions or mutations in the survival motor neuron gene, SMN, are responsible for the disease. There are two SMN genes. However, only telomeric copy (SMNt or SMNI) causes disease. Due to a single nucleotide difference, T in the second gene SMN2 from C in SMNI, the majority of SMN2 mRNA or protein skips exon7, resulting in an unstable SMNA7 protein and reduction of its oligomerization ability. Therefore, the presence of the SMN2 gene in SMA patients can not compensate for the loss of the SMNI gene. To understand the pathogenesis of SMA, the first goal of this proposal is to use the yeast two-hybrid screens to identify SMN interacting proteins, particularly those from motor neurons. The interactions will be further characterized by other complementary methods including mammalian two hybrid assays, in vitro binding assays and in vivo co-immunoprecipitation assays. The biological significance of interactions between SMN and its interactors will be investigated in cell lines, and as long-term goals, in animal models. The second goal of this proposal is to develop cell-based systems for therapeutic studies of SMA based on the hypothesis that increasing of total or full-length SMN protein from SMN2 would reduce the severity of SMA. Stable cell lines and transgenic mice expressing exon 7 splicing cassettes with reporters such as GFP, luciferase or P-lactamase will be established. Both high and low throughput screening (HTS, LTS) will be used to identify small molecules to promote inclusion of exon 7 in SMN2 mRNA and protein. These compounds will be tested in SMA mouse models. Signal pathways and other mechanisms that regulate RNA splicing of SMN genes will be investigated. 1 ZNS1 SRB R(01) 3 1 R01 NS41665-01 DECEMBER 13-14, 2000 ZHOU, DR. JIANHUA

描述（由申请人提供）：

项目成果

SMN protects cells against mutant SOD1 toxicity by increasing chaperone activity.

SMN 通过增加伴侣活性来保护细胞免受突变型 SOD1 毒性。

• DOI: 10.1016/j.bbrc.2007.10.096
• 发表时间: 2007
• 期刊: Biochemical and biophysical research communications
• 影响因子: 3.1
• 作者: Zou,Tie;Ilangovan,Raju;Yu,Furong;Xu,Zuoshang;Zhou,Jianhua
• 通讯作者: Zhou,Jianhua