Smad signaling in skeletal muscle laminopathies
Smad signaling in skeletal muscle laminopathies
批准号:
9895098
负责人:
Lori L Wallrath
金额:
$20.39万
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
项目状态:
已结题
起止时间:
2020-03-01 至 2022-02-28
关键词:
AgingAllelesAntibodiesBioinformaticsBiological AssayBiopsyCessation of lifeCritical PathwaysCytologyDNA SequenceDNA sequencingDataDaughterDefectDiabetes MellitusDifferentiation and GrowthDiseaseDrosophila genusEmery-Dreifuss Muscular DystrophyExhibitsFamilyFamily memberGene-ModifiedGenesGenomic DNAHealthHomeostasisHumanIndividualIntermediate FilamentsLaboratoriesLaminsLimb structureMADH7 geneMetabolic syndromeModelingMorphologyMuscleMuscle functionMuscular AtrophyMuscular DystrophiesMutationMyopathyNuclear EnvelopePathologicPathway interactionsPhenotypePhysiciansPupaRare DiseasesSeveritiesSeverity of illnessSignal PathwaySignal TransductionSkeletal MuscleStainsTestingTissuesTransforming Growth Factor betaTransgenesVariantage relatedcell motilitycommon symptomcongenital muscular dystrophydisease phenotypedisease-causing mutationearly onsetenv Gene Productsexperimental studygenome sequencinginhibitor/antagonistinsightloss of functionmembermutantnew therapeutic targetnovelnovel therapeuticsoverexpressionskeletaltargeted treatmenttherapy developmentwhole genome
中文摘要
科学文摘
英文摘要
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.
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Smad signaling in skeletal muscle laminopathies
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批准号:10116286
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项目类别:
-
资助金额:$16.49万
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财政年份:2020
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负责人:Lori L Wallrath
-
依托单位:
The role of lamins in transcription and redox homeostasis
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批准号:8691734
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项目类别:
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资助金额:$19.25万
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财政年份:2013
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负责人:Lori L Wallrath
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依托单位:
The role of lamins in transcription and redox homeostasis
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批准号:8568452
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项目类别:
-
资助金额:$16.04万
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财政年份:2013
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负责人:Lori L Wallrath
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依托单位:
Drosophila as a model for Emery-Dreifuss muscular dystrophy
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批准号:8103815
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项目类别:
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资助金额:$13.17万
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财政年份:2010
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负责人:Lori L Wallrath
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依托单位:
Drosophila as a model for Emery-Dreifuss muscular dystrophy
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批准号:7982911
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项目类别:
-
资助金额:$25.66万
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财政年份:2010
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负责人:Lori L Wallrath
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依托单位:
Mechanisms of Gene Silencing
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批准号:7146494
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项目类别:
-
资助金额:$29.87万
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财政年份:2001
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负责人:Lori L Wallrath
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依托单位:
Mechanisms of Gene Silencing
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批准号:6636474
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项目类别:
-
资助金额:$24.4万
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财政年份:2001
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负责人:Lori L Wallrath
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依托单位:
Mechanisms of Gene Silencing
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批准号:6904659
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项目类别:
-
资助金额:$24.91万
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财政年份:2001
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负责人:Lori L Wallrath
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依托单位:
Mechanisms of Gene Silencing
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批准号:7341877
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项目类别:
-
资助金额:$0.99万
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财政年份:2001
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负责人:Lori L Wallrath
-
依托单位:
Mechanisms of Gene Silencing
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批准号:6520275
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项目类别:
-
资助金额:$24.4万
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财政年份:2001
-
负责人:Lori L Wallrath
-
依托单位:
Mechanisms of Gene Silencing
-
批准号:6792258
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项目类别:
-
资助金额:$1.69万
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财政年份:2001
-
负责人:Lori L Wallrath
-
依托单位:
Mechanisms of Gene Silencing
-
批准号:7643811
-
项目类别:
-
资助金额:$29.14万
-
财政年份:2001
-
负责人:Lori L Wallrath
-
依托单位:
Mechanisms of Gene Silencing
-
批准号:6323802
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项目类别:
-
资助金额:$26.75万
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财政年份:2001
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负责人:Lori L Wallrath
-
依托单位:
Mechanisms of Gene Silencing
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批准号:7253126
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项目类别:
-
资助金额:$29.99万
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财政年份:2001
-
负责人:Lori L Wallrath
-
依托单位:
Mechanisms of Gene Silencing
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批准号:6767762
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项目类别:
-
资助金额:$26.57万
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财政年份:2001
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负责人:Lori L Wallrath
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依托单位:
HETEROCHROMATIN STRUCTURE AND GENE REPRESSION
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批准号:2169104
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项目类别:
-
资助金额:$2.86万
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财政年份:1993
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负责人:Lori L Wallrath
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依托单位:
HETEROCHROMATIN STRUCTURE AND GENE REPRESSION
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批准号:3046082
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项目类别:
-
资助金额:$2.27万
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财政年份:1992
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负责人:Lori L Wallrath
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依托单位:
HETEROCHROMATIN STRUCTURE AND GENE REPRESSION
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批准号:3046081
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项目类别:
-
资助金额:$2.16万
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财政年份:1991
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负责人:Lori L Wallrath
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依托单位:
海外基金