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Notch Signaling in non-myogenic mesenchymal cells regulates muscle development

非肌源性间充质细胞中的 Notch 信号传导调节肌肉发育

基本信息

批准号：
10397075
负责人：
Abigail leinroth
金额：
$ 3.92万
依托单位：
DUKE UNIVERSITY
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：
2020-05-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10397075
关键词：
Address Adipocytes Adult Affect Cell physiology Cell surface Cells Deposition Development Disease Extracellular Matrix Fatty acid glycerol esters Fibronectins Flow Cytometry Future Hand Strength Immunofluorescence Immunologic Impairment In Situ In Vitro Individual Knowledge MCAM gene Mediating Mesenchymal Mesenchymal Stem Cells Methods Modeling Molecular Muscle Muscle Development Muscle function Myoblasts Myopathy Natural regeneration PDGFRB gene Pericytes Peroxisome Proliferator-Activated Receptors Population Regulation Research Role Signal Transduction Skeletal Muscle Smooth Muscle Myocytes Stains Testing Time Transgenes Vascular Smooth Muscle Vimentin Western Blotting Work adiponectin histological stains in vivo insight interstitial lipid biosynthesis loss of function muscle regeneration myogenesis notch protein novel postnatal prevent progenitor single-cell RNA sequencing

项目摘要

ABSTRACT The majority of research on muscle development focuses on the specific regulation and direct contribution of myogenic progenitors and myoblasts to muscle formation. Recently, non-myogenic mesenchymal cells (NMMCs) located within developing muscle tissues have been identified as critical regulators of normal myogenesis. These studies show that muscle development or regeneration cannot occur in the absence of specific non-myogenic mesenchymal “niche” cells. In order to genetically examine regulatory mechanisms that may be critical for NMMC function and normal muscle development, our lab has demonstrated the utility of the Prx1Cre in accessing the broad class of NMMCs within skeletal muscle. Flow cytometry and scRNA sequencing of the Prx1 lineage not only confirmed that multiple populations of NMMCs exist within the skeletal muscle, but also that these populations are responsive to NOTCH signaling. Further, preliminary results indicate that a conditional loss of NOTCH within NMMCs (NOTCH LOF, Prx1Cre; RBPJkf/f) impairs normal muscle development and function. Given this, we hypothesize that NOTCH mediated regulation of NMMCs is critical for normal skeletal muscle development and function. In testing this hypothesis, we will utilize a combination of in vivo and in vitro methods in order to: (Aim 1) determine the role of NOTCH signaling in non-myogenic mesenchymal progenitors during muscle development in vivo and (Aim 2) evaluate the cellular mechanisms by which NMMC-mediated NOTCH signaling regulates skeletal muscle in vitro. Our findings will further our fundamental understanding of muscle development, specifically, our understanding of niche regulation and dynamics during muscle formation and function. Additionally, these findings may provide key insights into the role(s) of NMMC-derived NOTCH signaling in diseases affecting muscle development, and may also aid in future studies of muscle regeneration where disruption of the NMMC niche prevents proper myogenesis.

摘要