The role of connective tissue in regulating muscularization and innervation of the diaphragm
结缔组织在调节膈肌肌肉化和神经支配中的作用
基本信息
- 批准号:9754651
- 负责人:
- 金额:$ 6.37万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-08-01 至 2020-07-31
- 项目状态:已结题
- 来源:
- 关键词:AbdomenAbdominal CavityAffectAmbystomaAxonBiochemistryBiological ModelsBirthCell Culture TechniquesCellsCervical spinal cord structureChemotactic FactorsChestCoculture TechniquesCongenital AbnormalityCongenital diaphragmatic herniaConnective TissueDataDefectDevelopmentEmbryoEmbryologyEmbryonic StructuresFibroblastsGene ExpressionGeneticHGF geneImageIncidenceInjectionsLiverMAP Kinase GeneMicroscopyMolecularMorbidity - disease rateMorphogenesisMotorMusMuscleMuscle DevelopmentMutagenesisMutationNeonatal MortalityNerveNeural tubeNeuromuscular JunctionPathway interactionsPatternPlayPropertyResearchRespirationRespiratory DiaphragmRespiratory ParalysisRoleSignal TransductionSkeletal MuscleSomitesSourceStructure of phrenic nerveTechniquesTendon structureTestingThoracic cavity structureTrainingaxon guidanceaxonal guidancebonecareerconfocal imagingexperienceexperimental studyinnovationlung developmentmigrationmortalitymouse modelnerve supplynovel strategiesprogenitorprotein expressionrecruitskillsspatiotemporaltwo-photon
项目摘要
Project Summary
The diaphragm is an essential skeletal muscle, playing a critical role in respiration and serving as a barrier
that separates the thoracic and abdominal cavities. Development of the diaphragm requires the integration of
muscle, connective tissue, tendon, bone, and nerves that arise from different embryonic sources. Defects in
muscularization of the diaphragm cause congenital diaphragmatic hernias (CDH), a common birth defect (1 in
3,000 births) where the liver herniates into the thorax, impeding lung development and resulting in a 50%
neonatal mortality rate. Diaphragm development entails the migration of muscle precursors from the somites
and the extension phrenic nerve axons (the sole source of innervation) to connective tissue progenitors.
However, in spite of the high incidence of CDH and functional importance of the diaphragm, the cellular
interactions and molecular signals directing muscle migration and axon guidance required for diaphragm
muscularization and innervation are largely unknown and the subject of this proposal. Our lab has recently
demonstrated that interactions between muscle and connective tissue are crucial for normal development of
the diaphragm muscle and defects in this interaction are a source of CDH. The muscle connective tissue
originates from transient embryonic structures, termed the pleuroperitoneal folds (PPFs). This project focuses
on the role of PPFs and, in particular, Hepatocyte Growth Factor (HGF) secreted by the PPFs, in guiding
muscle progenitors and the phrenic nerve to the developing diaphragm. Preliminary data showing the
expression of Met in the diaphragm's muscle progenitors and Hgf in PPF fibroblasts suggests that PPF-derived
HGF is important for recruiting MET+ muscle progenitors into the developing diaphragm. However, an earlier
MET requirement for delamination of progenitors from the somites has precluded an explicit test of this
hypothesis. Aim 1 will determine which somites are the source of diaphragm muscle and test the hypothesis
that HGF is an important PPF-derived secreted signal that critically regulates migration of muscle into and
throughout the diaphragm. By conditional deletion of Hgf in PPFs after muscle progenitors have emigrated
from the somite, I will test the role of HGF/MET signaling in muscle progenitor migration into the diaphragm.
Preliminary data suggest that loss of PPF-derived Hgf disrupts normal muscularization and guidance of phrenic
nerve axons into the diaphragm. Aim 2 will test the hypothesis that PPF and muscle derived signals are
required for guiding phrenic nerve axons to and throughout the diaphragm. I will determine whether the
pleuroperitoneal folds have chemoattractant properties in culture and characterize how the depletion of
secreted signals, including Hgf, affect the guidance of phrenic nerve axons. Taken together, these studies
exploit the powerful genetics of mice to define the role of connective tissue progenitors in muscle migration and
axon guidance to the developing diaphragm and establish a basis for understanding how connective tissue
defects can contribute to congenital diaphragmatic hernias.
项目摘要
横膈膜是一种重要的骨骼肌,在呼吸中起着关键作用,并充当屏障
分隔胸腔和腹腔隔膜的开发需要集成
肌肉、结缔组织、腱、骨和神经都是由不同的胚胎来源产生的。缺陷
膈肌肌化导致先天性膈疝(CDH),一种常见的出生缺陷(1例
3,000例出生),其中肝脏疝入胸腔,阻碍肺部发育,导致50%的
新生儿死亡率横膈膜的发育需要肌肉前体从体节迁移
以及延伸膈神经轴突(神经支配的唯一来源)到结缔组织祖细胞。
然而,尽管CDH的发病率很高,横膈膜的功能也很重要,
相互作用和分子信号指导肌肉迁移和轴突指导所需的隔膜
肌肉化和神经支配在很大程度上是未知的,也是本建议的主题。我们的实验室最近
证明肌肉和结缔组织之间的相互作用对于骨骼的正常发育至关重要
膈肌和这种相互作用中的缺陷是CDH的来源。肌肉结缔组织
起源于短暂的胚胎结构,称为胸膜腹膜褶皱(PPF)。该项目重点
PPF的作用,特别是PPF分泌的肝细胞生长因子(HGF),
肌肉祖细胞和膈神经到发育中的膈肌。初步数据显示,
Met在膈肌祖细胞中的表达和Hgf在PPF成纤维细胞中的表达表明PPF衍生的
HGF对于将MET+肌肉祖细胞募集到发育中的膈肌中是重要的。然而,早些时候,
MET对祖细胞与体节分层的要求排除了对此的明确测试
假说.目的1将确定哪些体节是膈肌的来源,并检验假设
HGF是一种重要的PPF来源的分泌信号,其关键性地调节肌肉向
整个横膈膜。通过肌肉祖细胞迁移后PPF中Hgf的条件性缺失
从体节,我将测试HGF/MET信号传导在肌肉祖细胞迁移到膈肌中的作用。
初步数据表明,PPF来源的Hgf的缺失破坏了正常的肌肉化和膈神经的引导。
神经轴突进入横膈膜目的2将检验PPF和肌肉衍生信号是
这是引导膈神经轴突到达并穿过横膈膜所必需的。我将决定
胸膜腹膜褶皱在培养中具有化学引诱物的特性,并表征了
包括Hgf在内的分泌信号影响膈神经轴突的导向。综合来看,这些研究
利用小鼠强大的遗传学来确定结缔组织祖细胞在肌肉迁移中的作用,
轴突指导发展中的隔膜,并建立一个基础,了解结缔组织如何
缺陷可能导致先天性腹股沟疝。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Elizabeth Marie Sefton其他文献
Elizabeth Marie Sefton的其他文献
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{{ truncateString('Elizabeth Marie Sefton', 18)}}的其他基金
Biophysical and genetic mechanisms underlying diaphragm morphogenesis and Congenital Diaphragmatic Hernias
膈肌形态发生和先天性膈疝的生物物理和遗传机制
- 批准号:
10224292 - 财政年份:2020
- 资助金额:
$ 6.37万 - 项目类别:
Biophysical and genetic mechanisms underlying diaphragm morphogenesis and Congenital Diaphragmatic Hernias
膈肌形态发生和先天性膈疝的生物物理和遗传机制
- 批准号:
10649889 - 财政年份:2020
- 资助金额:
$ 6.37万 - 项目类别:
The role of connective tissue in regulating muscularization and innervation of the diaphragm
结缔组织在调节膈肌肌肉化和神经支配中的作用
- 批准号:
9542656 - 财政年份:2017
- 资助金额:
$ 6.37万 - 项目类别:
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