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Investigating how Mylpf-regulated sarcomere formation influences limb skeletal development

研究 Mylpf 调节的肌节形成如何影响肢体骨骼发育

基本信息

批准号：
10437165
负责人：
Jared Coffin Talbot
金额：
$ 43.34万
依托单位：
UNIVERSITY OF MAINE ORONO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10437165
关键词：
Actins Affect Alleles Arthrogryposis Binding Proteins Birth Cartilage Chemicals Congenital Abnormality Congenital clubfoot Contracts Contracture Defect Deformity Development Disease Disease model Distal Embryo Embryonic Development Fishes Genes Hand Head Heat-Shock Response Human Image Imaging Device Impairment Joints Label Larva Lead Limb structure Link Live Birth Modeling Movement Muscle Muscle Contraction Muscle Development Muscle Fibers Muscle function Musculoskeletal Musculoskeletal Development Musculoskeletal Diseases Mutation Myosin ATPase Myosin Heavy Chains Myosin Light Chains Myosin Type II Nonmuscle Myosin Type IIA Operative Surgical Procedures Paralysed Patients Phenotype Proteins Role Sarcomeres Skeletal Development Skeleton Stigmatization Testing Thick Thick Filament Thin Filament Transgenic Organisms Variant Work Zebrafish arthropathies base chronic pain foot genetic variant human disease human model in utero inhibitor innovation joint formation motor impairment mutant prevent restoration skeletal unpublished works

项目摘要

Investigating how Mylpf-regulated sarcomere formation influences limb skeletal development In arthrogryposis, babies are born with at least two limbs with hand or foot showing contractures; it most commonly manifests as clubfoot, and it is found in roughly 1 in 4000 live births. Arthrogryposis causes impaired movement and can require many surgeries through a lifetime to correct. The disease is characterized by skeletal joint defects, but it is caused by impaired muscle movement in utero. We recently found that the muscle-expressed gene Mylpf is vital not only to normal actin movement, but also for muscle fiber integrity and that variants in human MYLPF cause Distal Arthrogryposis Type 1 (DA1). Mylpf protein binds to the myosin heavy chain near head region which moves actin during muscle contraction. We discovered that zebrafish mylpfa mutant larvae display a phenotype consistent with DA1, including impaired myosin activity, reduced muscle force overall, and complete fin paralysis. Surprisingly, we find that Mylpf function is needed not only for normal contraction, but also for the assembly of actin and myosin into the fundamental unit of muscle, called sarcomeres. In unpublished work we find that sarcomeres form poorly in mylpfa mutants, lacking one of two Mylpf genes, and are completely absent in mylpfa;mylpfb double mutants, which lack all Mylpf function. We hypothesize that Mylpf function prevents distal arthrogryposis by promoting association of sarcomeric components during the critical window of embryonic development when limb joints are forming. To test this hypothesis, we will (Aim 1) investigate the role of Mylpf in sarcomere assembly, (Aim 2a) investigate how the human MYLPF gene variants cause this musculo-skeletal disease, and (Aim 2b) when the skeletal defects can be corrected.

研究mylpf调控的肌节形成如何影响肢体骨骼发育