Cellular Basis of Incisor Asymmetry

门牙不对称的细胞基础

基本信息

批准号：
10707930
负责人：
Ameera Samaher Haque
金额：
$ 5.35万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
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：
2022-09-01 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10707930
关键词：
3-Dimensional Affect Apoptosis Architecture Atlases Automobile Driving Behavior Biological Process Bone Resorption Cell Communication Cell Proliferation Cell Shape Cell Size Cell division Cells Cellular Morphology Computer software Cues Dental Dental Enamel Dental Schools Dentists Dentition Dentures Development Developmental Biology Disease Distal Embryo Embryonic Development Environment Epithelium Event Fellowship Foundations Future Genetic Goals Growth Image Implant Incisor Individual Intercalated Cell Investigation Journals Knowledge Mandible Maps Measurement Measures Mechanics Mediating Mentorship Mesenchymal Mesenchyme Modeling Molecular Morphogenesis Morphology Mus Natural regeneration Neck Nuclear Organ Organism Organogenesis Osseointegration Pathway interactions Positioning Attribute Process Proliferating Qualifying Research Resolution Role Rotation SHH gene Scientist Series Shapes Signal Transduction Signal Transduction Pathway Signaling Molecule Specimen Stratification Structure System Techniques Testing Tissues Tooth Germ Tooth regeneration Tooth structure Training Work age effect career cell behavior cell motility clinical training comparison control cyclopamine design digital driving behavior experimental study high resolution imaging improved in vivo insight meetings migration morphogens mutant novel pharmacologic programs regenerative regenerative approach regenerative therapy restorative dentistry small molecule inhibitor software development spatiotemporal tissue regeneration

3-Dimensional Affect Apoptosis Architecture Atlases Automobile Driving Behavior Biological Process Bone Resorption Cell Communication Cell Proliferation Cell Shape Cell Size Cell division Cells Cellular Morphology Computer software Cues Dental Dental Enamel Dental Schools Dentists Dentition Dentures Development Developmental Biology Disease Distal Embryo Embryonic Development Environment Epithelium Event Fellowship Foundations Future Genetic Goals Growth Image Implant Incisor Individual Intercalated Cell Investigation Journals Knowledge Mandible Maps Measurement Measures Mechanics Mediating Mentorship Mesenchymal Mesenchyme Modeling Molecular Morphogenesis Morphology Mus Natural regeneration Neck Nuclear Organ Organism Organogenesis Osseointegration Pathway interactions Positioning Attribute Process Proliferating Qualifying Research Resolution Role Rotation SHH gene Scientist Series Shapes Signal Transduction Signal Transduction Pathway Signaling Molecule Specimen Stratification Structure System Techniques Testing Tissues Tooth Germ Tooth regeneration Tooth structure Training Work age effect career cell behavior cell motility clinical training comparison control cyclopamine design digital driving behavior experimental study high resolution imaging improved in vivo insight meetings migration morphogens mutant novel pharmacologic programs regenerative regenerative approach regenerative therapy restorative dentistry small molecule inhibitor software development spatiotemporal tissue regeneration

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项目摘要

Project Summary Morphogenesis is the biological process by which cells, tissues, and organs acquire the shape that is critical to their function during embryonic development, and it can be repurposed during regeneration of tissues after damage in a mature organism. Work on embryonic explants has revealed that differences in cellular morphologies and mechanical cell-cell interactions, both controlled by signaling molecules, likely drive tissue- specific shapes in multiple epithelial tissues including the symmetric murine molar. Nevertheless, a deeper understanding of the basic principles and cellular behaviors that regulate morphogenesis is required to leverage these processes for future regenerative therapies that can mitigate the effects of aging and disease. I will use the early developmental stages of the murine incisor to study how cell behaviors drive directional growth and morphogenesis. Murine incisor development is highly asymmetric, and the mechanisms regulating this process have remained elusive. Prior studies have shown that perturbations in Sonic Hedgehog (Shh) signaling result in abnormal incisor morphology, and that Shh-dependent cell movement drives tooth bud invagination in the symmetrical molar. Through this proposal, I will test the hypothesis that modulation of the Shh signaling cascade drives changes in cellular morphology and behavior that determine the asymmetric morphogenic development of the incisor. I will measure and quantify localized cellular and tissue morphological changes such as cell shape, nuclear position, and tooth curvature, as well as dynamic cell behaviors such as differential proliferation, oriented cell division, and cell intercalation, using high resolution live imaging and our novel software program, MARGARITA. This will establish a foundational atlas of cell morphologies and behaviors responsible for the epithelial bending events driving early development of the asymmetric incisor (Aim 1). Next, pharmacological perturbation of Shh signaling in incisor explants and spatiotemporal modulation of Shh expression in genetic mutants will determine to what extent the modulation of this signal transduction pathway affects cellular morphology during incisor development (Aim 2). These findings will provide significant insights into basic tooth and developmental biology, which have the potential to be applied towards future dental regenerative therapies. Current strategies to restore missing dentition (i.e., implants, dentures) can lead to significant bone resorption or may fail due to limited osseointegration. Thus, biologically regenerating teeth using morphogenesis-driven techniques has the potential to significantly improve restorative dentistry. These research goals will be conducted in conjunction with a comprehensive training plan designed to develop my career as a dentist-scientist. Training includes structured mentorship from two highly qualified sponsors, as well as scientific and technical training through meetings, seminars, journal clubs, and classes at UCSF, which offers both an outstanding research environment and an excellent dental school for clinical training.

项目摘要形态发生是生物学过程，细胞，组织和器官获得至关重要的形状它们在胚胎发育过程中的功能，并且可以在组织再生期间进行重新使用成熟生物体的损害。关于胚胎外植体的工作表明细胞的差异形态和机械细胞 - 细胞相互作用，均由信号分子控制，可能驱动组织 - 包括对称鼠摩尔在内的多个上皮组织中的特定形状。然而，更深入需要了解调节形态发生的基本原理和细胞行为才能利用这些过程用于未来再生疗法，可以减轻衰老和疾病的影响。我将使用鼠门牙的早期发育阶段来研究细胞行为如何推动方向生长和形态发生。鼠牙发育是高度不对称的，调节的机制过程仍然难以捉摸。先前的研究表明，声音刺猬（SHH）信号的扰动导致异常的门牙形态，而SHH依赖性细胞运动驱动了牙齿芽的内陷对称磨牙。通过此提案，我将测试SHH信号调节的假设级联驱动细胞形态和行为的变化，这些变化决定了不对称形态的变化门牙的发展。我将测量和量化局部的细胞和组织形态变化，例如如细胞形状，核位置和牙齿曲率以及动态细胞行为（例如差异）使用高分辨率实时成像和我们的小说软件程序，玛格丽塔。这将建立一个细胞形态和行为的基础地图集负责上皮弯曲事件，推动了不对称门牙的早期发展（AIM 1）。下一个，切牙外植体中SHH信号传导的药理扰动和SHH的时空调制基因突变体中的表达将确定该信号转导途径的调制在多大程度上在门牙发育过程中影响细胞形态（AIM 2）。这些发现将提供重要的见解进入基本牙齿和发育生物学，有可能应用于未来的牙齿再生疗法。当前恢复缺失牙列的策略（即植入物，假牙）可能导致明显的骨吸收或可能由于有限的骨整合而失败。因此，使用生物学的牙齿使用形态发生驱动的技术具有显着改善修复牙科的潜力。这些研究目标将与旨在制定的全面培训计划一起实施我作为牙医科学家的职业。培训包括来自两个高素质赞助商的结构化指导，作为以及通过会议，研讨会，期刊俱乐部和UCSF上的科学和技术培训，提供出色的研究环境和出色的临床培训牙科学校。