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Defining Defects in Myosin Structure and Function That Cause Dominant Spondylocarpotarsal Synostosis

定义导致显性腕跗骨骨联结的肌球蛋白结构和功能缺陷

基本信息

批准号：
9899926
负责人：
Sanford I Bernstein
金额：
$ 19.87万
依托单位：
SAN DIEGO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9899926
关键词：
ATP phosphohydrolase Abnormal Cell Actin-Binding Protein Actins Adult Affect Affinity Alleles Animal Model Binding Biochemical Biological Models Biophysics Birth Cells Chest Congenital abnormal Synostosis Crystallization Cytoskeleton Defect Development Disease Dominant Genetic Conditions Drosophila genus Drosophila melanogaster Elements Embryo Filament Foot Deformities Functional disorder Genes Genetic Genetic Diseases Genetic Heterogeneity Goals Hand Hand deformities Heterotopic Ossification Human Human Genetics Intervertebral disc structure Joints Lead Link Maps Methods Modeling Molecular Molecular Structure Mus Muscle Muscle Proteins Muscle function Mutate Mutation Myofibrils Myosin ATPase Myosin Heavy Chains Nucleotides Pathology Phenotype Physiological Plant Roots Production Property Proteins Research Resolution Signal Transduction Skeletal Muscle Skeletal Muscle Myosins Standardization Structural defect Structure Structure-Activity Relationship System Testing Therapeutic Tissues Transgenic Model Transgenic Organisms Vertebral column alpha Actin base beta Actin bone causal variant cell motility cell type cost efficient design filamin foot genome sequencing human disease insight mechanical pressure muscular structure mutant postnatal relating to nervous system skeletal skeletal disorder spine bone structure vertebra body whole genome

项目摘要

PROJECT SUMMARY We propose to build and analyze the first animal models of dominant spondylocarpotarsal synostosis (SCT), a human genetic disease that arises from mutations in the MYH3 embryonic myosin heavy chain. These mutations yield misshaped and fused vertebral bodies as well as carpal and tarsal abnormalities that are hypothesized to arise from primary defects in muscle function. Our transgenic Drosophila melanogaster models will be used to dissect the biochemical, biophysical, developmental and physiological bases of this disease. The Drosophila system will allow us to mutate the Drosophila myosin gene to examine the effects of two SCT alleles in a standardized genetic background. This will define the importance of interactions between wild-type and mutant myosin molecules to disease pathology and will obviate genetic heterogeneity that leads to phenotypic variability in the human disease. Further we will explore the use of our transgenic system to produce adequate quantities of human wild-type and SCT MYH3 to determine their functional properties and solve their high-resolution crystal structures. We will test the following hypotheses: that actin binding, which influences nucleotide affinity and filament motility, is abnormal in the SCT mutant myosin models; that functionally abnormal SCT myosin leads to myofibril disruption and muscle dysfunction in the Drosophila model; that structure-function relationships about human myosin can be discerned using our Drosophila-based myosin expression system. To evaluate these hypotheses, we will pursue the following specific aims: 1) Assess the ATPase, actin binding and actin motility capabilities of mutant SCT myosins compared to the wild- type protein. 2) Determine the dominant effects of the mutations on myofibrillar ultrastructure and function of muscles from the larval body wall and adult thorax (indirect flight and jump muscles). 3) Explore the possibility of producing, isolating and determining the structural and functional properties of normal and SCT human MYH3 protein using a unique indirect flight muscle expression system. This multifaceted approach will provide mechanistic insights into the molecular and developmental bases of SCT and begin to elucidate how mutations in a skeletal muscle protein lead to developmental defects in associated skeletal elements. Understanding the underlying muscle defects causative of the disease may ultimately yield therapeutic approaches.

项目总结