Investigating collective myocardial cell movement during heart tube formation

研究心管形成过程中心肌细胞的集体运动

• 批准号: 10439340
• 负责人: Joshua Eli Bloomekatz
• 金额: $ 41.2万
• 依托单位: UNIVERSITY OF MISSISSIPPI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10439340
• 关键词: Ablation; Affect; Animal Model; Anterior; Architecture; Automobile Driving; Bilateral; Biological; Biomechanics; Cardiac; Cardiac Myocytes; Cardiovascular system; Cell Shape; Cell Size; Cell physiology; Cells; Communication; Congenital Abnormality; Data; Defect; Development; Developmental Biology; Disease; Educational process of instructing; Endoderm; Environment; Etiology; Event; Exhibits; Foundations; Future; Genes; Genetic; Genetic Techniques; Goals; Heart; Heart Abnormalities; Heart Diseases; Image; Individual; Laboratories; Lasers; Lateral; Lead; Ligands; Location; Medial; Mediating; Mesoderm; Mission; Mississippi; Molecular; Morphogenesis; Movement; Mus; Mutation; Myocardial; Myocardial dysfunction; Myocardium; Organ; Organogenesis; Pathogenesis; Pathway interactions; Pattern; Platelet-Derived Growth Factor; Platelet-Derived Growth Factor alpha Receptor; Population; Process; Property; Pseudopodia; Regulation; Research; Resolution; Rest; Rheology; Role; Signal Transduction; Signaling Molecule; Students; Techniques; Testing; Time; Tissues; Training; Transgenes; Tube; Universities; Vertebrates; Zebrafish; base; cardiogenesis; cell behavior; cell motility; citizen science; genetic analysis; graduate student; in vivo; insight; mutant; paracrine; programs; response; small molecule inhibitor; source localization; undergraduate student; university student; viscoelasticity

Project Summary Organ formation is critically regulated by inter-tissue communication. The architecture of the mature heart is a result of sequential morphogenetic events, starting with the primitive heart tube, which is the foundation upon which the rest of the heart is built. The process of building the primitive heart tube starts with the collective movement of myocardial cells from bilateral locations in the anterior lateral plate mesoderm to the midline, a process called cardiac fusion which is conserved in all vertebrates. Genetic analysis has revealed that the adjacent endoderm is critical for these movements. However, the signals or molecules by which the endoderm communicates to the myocardium remain unknown. Furthermore, the molecular mechanism by which myocardial cells in vertebrates respond to these signals and collectively move towards the midline is also poorly understood. To elucidate these mechanisms, undergraduate and graduate students from the University of Mississippi will take a multi-dimensional approach examining cardiac fusion at the tissue, molecular, cellular and biomechanical level. We have found that mutations in the Platelet-derived growth factor receptor alpha (Pdgfra) leads to cardiac fusion defects in both zebrafish and mice. Myocardial movement appears to occur in response to a localized source of the PDGF ligand pdgf-aa, which we found is expressed in the endoderm medially adjacent to pdgfra expression in the myocardium. Furthermore, our preliminary data reveals that disruption of PI3K signaling in zebrafish also causes cardiac fusion defects. And that myocardial cells exhibit protrusions and display heterogenous changes in cell shape during cardiac fusion. Together, this data suggests the hypothesis that paracrine PDGF signals from the endoderm activates Pdgfra-mediated PI3K signaling in the myocardium to create medial oriented migratory protrusions which create asymmetric biomechanical tension in the myocardium facilitating medial movement. We will test this hypothesis by using tissue- specific genetic techniques to determine the tissues in which pdgfra and pdgf-aa function (Aim 1) as well as determine whether PI3K signaling and migratory protrusions are activated downstream of Pdgfra (Aim2). Additionally, we will use micro-rheology and micro-laser ablation in combination with pdgfra mutants to examine the biomechanical properties in the myocardium controlled by PDGF signaling (Aim 3). In summary, these studies are likely to elucidate the molecular mechanisms that underlie how myocardial cells sense and respond to their local environment and in the long-term identify the fundamental principles that underlie cardiac morphogenesis in both development and disease. Furthermore, this proposal will help to establish a research program that intertwines student research opportunities with the discovery of fundamental molecular mechanisms underlying inter-tissue communication during organ morphogenesis.

项目总结