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Smad signaling in skeletal muscle laminopathies

骨骼肌纤层蛋白病中的 Smad 信号传导

基本信息

批准号：
10116286
负责人：
Lori L Wallrath
金额：
$ 16.49万
依托单位：
UNIVERSITY OF IOWA
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：
2020-03-01 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10116286
关键词：
Aging Alleles Antibodies Bioinformatics Biological Assay Biopsy Cessation of life Critical Pathways Cytology DNA Sequence DNA sequencing Data Daughter Defect Diabetes Mellitus Differentiation and Growth Disease Drosophila genus Emery-Dreifuss Muscular Dystrophy Exhibits Family Family member Gene-Modified Genes Genomic DNA Health Homeostasis Human Individual Intermediate Filaments Laboratories Lamins Limb structure MADH7 gene Metabolic syndrome Modeling Morphology Muscle Muscle function Muscular Atrophy Muscular Dystrophies Mutation Myopathy Nuclear Envelope Pathologic Pathway interactions Phenotype Physicians Pupa Rare Diseases Severities Severity of illness Signal Pathway Signal Transduction Skeletal Muscle Stains Testing Tissues Transforming Growth Factor beta Transgenes Variant age related cell motility common symptom congenital muscular dystrophy disease phenotype disease-causing mutation early onset env Gene Products experimental study genome sequencing inhibitor/antagonist insight loss of function member mutant new therapeutic target novel novel therapeutics overexpression skeletal targeted treatment therapy development whole genome

项目摘要

Scientific Abstract Mutations in the human LMNA gene encoding lamins cause skeletal muscular dystrophy that exhibits a wide range of disease severity, even among family members possessing the identical mutation. This observation suggests the action of modifier genes. To identify candidate modifier genes, whole genome sequencing (WGS) was performed on members of a family with LMNA Emery-Dreifuss muscular dystrophy (EDMD2) (c.1580G>C; p.R527P). The analysis revealed a novel variant in the SMAD7 gene (c.932A.G; p.Q311R) that segregated with disease severity. SMAD7 encodes an inhibitor of the conserved TGF-β/Smad signaling pathway. Activation of this pathway due to reduced levels of SMAD7 represses muscle growth and differentiation and causes loss of muscle tissue homeostasis. Using a Drosophila model of LMNA muscular dystrophy, we found that over-expression of the Drosophila orthologue of SMAD7 suppressed lethality caused by mutant lamins. To test the hypothesis that Smad signaling modifies muscle phenotypes induced by mutant lamins, we will 1) alter Smad signaling and assay for effects on muscle phenotypes in Drosophila models of LMNA muscle disease and 2) perform WGS on another family with an LMNA mutation in which members exhibit either severe or asymptomatic muscle disease phenotypes. In addition, we will analyze TGF-β/Smad signaling in muscle biopsy tissue from individuals with LMNA muscular dystrophy. Collectively, our experiments will determine the interplay between TGF-β/Smad signaling and lamins in skeletal muscle disease and identify candidate modifier genes are potential targets for therapy. Our discoveries have the potential for broad impact as individuals with LMNA muscle disease have symptoms of common diseases such as diabetes and metabolic syndrome.

科学抽象编码核纤层蛋白的人LMNA基因的突变引起骨骼肌营养不良，表现出广泛的疾病严重程度，即使在家庭成员拥有相同的突变这一观察结果表明了修饰基因的作用。识别候选修改量基因，全基因组测序（WGS）进行了一个家庭的成员与LMNA Emery-Dreifuss肌营养不良症（EDMD 2）（c.1580G>C; p.R527P）。分析显示， SMAD 7基因（c.932A.G; p.Q311R）中的新变体，其随疾病严重程度分离。 SMAD 7编码保守的TGF-β/Smad信号通路的抑制剂。激活此由于SMAD 7水平降低导致的途径抑制肌肉生长和分化，肌肉组织失去平衡使用LMNA肌营养不良症的果蝇模型，我们发现过表达SMAD 7的果蝇直向同源物抑制致死性，突变核纤层蛋白为了验证Smad信号改变肌肉表型的假设，通过突变核纤层蛋白诱导，我们将1）改变Smad信号传导并测定对肌肉的影响表型的果蝇模型的LMNA肌肉疾病和2）进行WGS对另一个一个LMNA突变的家族，其中成员表现出严重或无症状的肌肉疾病表型此外，我们还将分析肌肉活检组织中TGF-β/Smad信号传导，来自患有LMNA肌营养不良症的个体。总的来说，我们的实验将决定 TGF-β/Smad信号通路与层粘连蛋白在骨骼肌疾病中相互作用及其鉴定候选修饰基因是潜在的治疗靶点。我们的发现有可能广泛的影响，因为患有LMNA肌肉疾病的个体具有常见疾病的症状例如糖尿病和代谢综合征。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Drosophila Models Reveal Properties of Mutant Lamins That Give Rise to Distinct Diseases.

DOI：
10.3390/cells12081142
发表时间：
2023-04-12
期刊：
Cells
影响因子：
6
作者：
通讯作者：

Modulation of muscle redox and protein aggregation rescues lethality caused by mutant lamins.

肌肉氧化还原和蛋白质聚集的调节可挽救突变核纤层蛋白引起的致命性。

DOI：
10.1016/j.redox.2021.102196
发表时间：
2021-11-25
期刊：
Redox biology
影响因子：
11.4
作者：
Coombs GS;Rios-Monterrosa JL;Lai S;Dai Q;Goll AC;Ketterer MR;Valdes MF;Uche N;Benjamin IJ;Wallrath LL
通讯作者：
Wallrath LL

In Silico and In Vivo Analysis of Amino Acid Substitutions That Cause Laminopathies.